JP2009261402A - 筋重量を増加させるためのフォリスタチンの使用方法 - Google Patents
筋重量を増加させるためのフォリスタチンの使用方法 Download PDFInfo
- Publication number
- JP2009261402A JP2009261402A JP2009147316A JP2009147316A JP2009261402A JP 2009261402 A JP2009261402 A JP 2009261402A JP 2009147316 A JP2009147316 A JP 2009147316A JP 2009147316 A JP2009147316 A JP 2009147316A JP 2009261402 A JP2009261402 A JP 2009261402A
- Authority
- JP
- Japan
- Prior art keywords
- myostatin
- receptor
- gdf
- animal
- muscle
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 210000003205 muscle Anatomy 0.000 title claims abstract description 77
- 108010014612 Follistatin Proteins 0.000 title claims description 21
- 102000016970 Follistatin Human genes 0.000 title claims description 18
- 108010056852 Myostatin Proteins 0.000 claims abstract description 565
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 402
- 238000000034 method Methods 0.000 claims abstract description 233
- 241001465754 Metazoa Species 0.000 claims abstract description 110
- 230000000694 effects Effects 0.000 claims abstract description 101
- 230000001965 increasing effect Effects 0.000 claims abstract description 31
- 102100039939 Growth/differentiation factor 8 Human genes 0.000 claims description 533
- 108020003175 receptors Proteins 0.000 claims description 372
- 102000005962 receptors Human genes 0.000 claims description 368
- 210000004027 cell Anatomy 0.000 claims description 286
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 207
- 229920001184 polypeptide Polymers 0.000 claims description 163
- 108090000623 proteins and genes Proteins 0.000 claims description 101
- 230000014509 gene expression Effects 0.000 claims description 70
- 230000009261 transgenic effect Effects 0.000 claims description 58
- 241000282414 Homo sapiens Species 0.000 claims description 55
- 125000000539 amino acid group Chemical group 0.000 claims description 48
- 230000027455 binding Effects 0.000 claims description 48
- 108020004414 DNA Proteins 0.000 claims description 47
- 108700019146 Transgenes Proteins 0.000 claims description 37
- 108010076504 Protein Sorting Signals Proteins 0.000 claims description 33
- 239000000488 activin Substances 0.000 claims description 30
- 150000007523 nucleic acids Chemical group 0.000 claims description 30
- 108010059616 Activins Proteins 0.000 claims description 29
- 108091028043 Nucleic acid sequence Proteins 0.000 claims description 26
- 101100437153 Rattus norvegicus Acvr2b gene Proteins 0.000 claims description 26
- 125000003275 alpha amino acid group Chemical group 0.000 claims description 25
- 235000019688 fish Nutrition 0.000 claims description 25
- 241000251468 Actinopterygii Species 0.000 claims description 24
- 230000002401 inhibitory effect Effects 0.000 claims description 24
- 238000012360 testing method Methods 0.000 claims description 24
- 241000894007 species Species 0.000 claims description 21
- 102000039446 nucleic acids Human genes 0.000 claims description 20
- 108020004707 nucleic acids Proteins 0.000 claims description 20
- 210000001519 tissue Anatomy 0.000 claims description 20
- 230000001105 regulatory effect Effects 0.000 claims description 19
- 241000238557 Decapoda Species 0.000 claims description 18
- 210000001161 mammalian embryo Anatomy 0.000 claims description 16
- 235000013305 food Nutrition 0.000 claims description 15
- 108091000080 Phosphotransferase Proteins 0.000 claims description 13
- 210000004602 germ cell Anatomy 0.000 claims description 13
- 238000000338 in vitro Methods 0.000 claims description 13
- 102000020233 phosphotransferase Human genes 0.000 claims description 13
- 241000283690 Bos taurus Species 0.000 claims description 12
- 238000004519 manufacturing process Methods 0.000 claims description 12
- 239000003623 enhancer Substances 0.000 claims description 11
- 241000124008 Mammalia Species 0.000 claims description 10
- 235000013601 eggs Nutrition 0.000 claims description 10
- 108010052946 Activin Receptors Proteins 0.000 claims description 9
- 241000972773 Aulopiformes Species 0.000 claims description 9
- 241000271566 Aves Species 0.000 claims description 9
- 210000000663 muscle cell Anatomy 0.000 claims description 9
- 238000012545 processing Methods 0.000 claims description 9
- 235000019515 salmon Nutrition 0.000 claims description 9
- 102000018918 Activin Receptors Human genes 0.000 claims description 8
- 241000237858 Gastropoda Species 0.000 claims description 8
- 241000287828 Gallus gallus Species 0.000 claims description 7
- 102000016349 Myosin Light Chains Human genes 0.000 claims description 7
- 108010067385 Myosin Light Chains Proteins 0.000 claims description 7
- 241001494479 Pecora Species 0.000 claims description 7
- 235000013330 chicken meat Nutrition 0.000 claims description 7
- 230000002950 deficient Effects 0.000 claims description 7
- 235000020637 scallop Nutrition 0.000 claims description 7
- 241000237519 Bivalvia Species 0.000 claims description 6
- 241000237503 Pectinidae Species 0.000 claims description 6
- 235000020639 clam Nutrition 0.000 claims description 6
- 241000238565 lobster Species 0.000 claims description 6
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 claims description 5
- 241000237502 Ostreidae Species 0.000 claims description 5
- 235000020636 oyster Nutrition 0.000 claims description 5
- 241000243818 Annelida Species 0.000 claims description 4
- 244000132059 Carica parviflora Species 0.000 claims description 4
- 235000014653 Carica parviflora Nutrition 0.000 claims description 4
- 241000252212 Danio rerio Species 0.000 claims description 4
- 210000002459 blastocyst Anatomy 0.000 claims description 4
- 230000013011 mating Effects 0.000 claims description 4
- 235000009899 Agrostemma githago Nutrition 0.000 claims description 3
- 241000252229 Carassius auratus Species 0.000 claims description 3
- 241001609213 Carassius carassius Species 0.000 claims description 3
- 241000252233 Cyprinus carpio Species 0.000 claims description 3
- 241000257465 Echinoidea Species 0.000 claims description 3
- 241001235208 Farfantepenaeus paulensis Species 0.000 claims description 3
- 241000251511 Holothuroidea Species 0.000 claims description 3
- 241001417534 Lutjanidae Species 0.000 claims description 3
- 241000237536 Mytilus edulis Species 0.000 claims description 3
- 241000238552 Penaeus monodon Species 0.000 claims description 3
- 241000269908 Platichthys flesus Species 0.000 claims description 3
- 241000287531 Psittacidae Species 0.000 claims description 3
- 241000277331 Salmonidae Species 0.000 claims description 3
- 241000269851 Sarda sarda Species 0.000 claims description 3
- 241000269821 Scombridae Species 0.000 claims description 3
- 241000270666 Testudines Species 0.000 claims description 3
- 244000178320 Vaccaria pyramidata Species 0.000 claims description 3
- 235000020640 mackerel Nutrition 0.000 claims description 3
- 235000020638 mussel Nutrition 0.000 claims description 3
- 210000003101 oviduct Anatomy 0.000 claims description 3
- 235000019512 sardine Nutrition 0.000 claims description 3
- 241000238017 Astacoidea Species 0.000 claims description 2
- 241000270722 Crocodylidae Species 0.000 claims description 2
- 241001417495 Serranidae Species 0.000 claims description 2
- 241000282898 Sus scrofa Species 0.000 claims description 2
- 241000269838 Thunnus thynnus Species 0.000 claims description 2
- 238000012258 culturing Methods 0.000 claims description 2
- 210000001672 ovary Anatomy 0.000 claims description 2
- 102000005606 Activins Human genes 0.000 claims 12
- 102000002322 Egg Proteins Human genes 0.000 claims 1
- 108010000912 Egg Proteins Proteins 0.000 claims 1
- 241000935974 Paralichthys dentatus Species 0.000 claims 1
- 241001125046 Sardina pilchardus Species 0.000 claims 1
- 241001441726 Tetraodontiformes Species 0.000 claims 1
- 239000000872 buffer Substances 0.000 claims 1
- LNNWVNGFPYWNQE-GMIGKAJZSA-N desomorphine Chemical compound C1C2=CC=C(O)C3=C2[C@]24CCN(C)[C@H]1[C@@H]2CCC[C@@H]4O3 LNNWVNGFPYWNQE-GMIGKAJZSA-N 0.000 claims 1
- 239000013613 expression plasmid Substances 0.000 claims 1
- 230000010807 negative regulation of binding Effects 0.000 claims 1
- 210000004681 ovum Anatomy 0.000 claims 1
- 210000000577 adipose tissue Anatomy 0.000 abstract description 23
- 239000000126 substance Substances 0.000 abstract description 23
- 230000019491 signal transduction Effects 0.000 abstract description 22
- 230000012010 growth Effects 0.000 abstract description 13
- 238000011161 development Methods 0.000 abstract description 12
- 230000002503 metabolic effect Effects 0.000 abstract description 10
- 230000002159 abnormal effect Effects 0.000 abstract description 9
- 230000004069 differentiation Effects 0.000 abstract description 8
- 230000001575 pathological effect Effects 0.000 abstract description 2
- 102000004472 Myostatin Human genes 0.000 abstract 5
- 239000003795 chemical substances by application Substances 0.000 description 178
- 102000040430 polynucleotide Human genes 0.000 description 154
- 108091033319 polynucleotide Proteins 0.000 description 154
- 239000002157 polynucleotide Substances 0.000 description 154
- 230000011664 signaling Effects 0.000 description 114
- 241000699670 Mus sp. Species 0.000 description 76
- 239000013598 vector Substances 0.000 description 57
- 102000004169 proteins and genes Human genes 0.000 description 49
- 125000003729 nucleotide group Chemical group 0.000 description 48
- 239000012634 fragment Substances 0.000 description 46
- 235000018102 proteins Nutrition 0.000 description 46
- 230000003993 interaction Effects 0.000 description 42
- 239000002773 nucleotide Substances 0.000 description 41
- 235000001014 amino acid Nutrition 0.000 description 38
- 229940024606 amino acid Drugs 0.000 description 33
- 150000001413 amino acids Chemical class 0.000 description 32
- 239000013604 expression vector Substances 0.000 description 30
- 239000000203 mixture Substances 0.000 description 29
- 230000000692 anti-sense effect Effects 0.000 description 28
- 230000002797 proteolythic effect Effects 0.000 description 28
- 230000035772 mutation Effects 0.000 description 26
- 210000004899 c-terminal region Anatomy 0.000 description 25
- 208000008589 Obesity Diseases 0.000 description 24
- 235000020824 obesity Nutrition 0.000 description 23
- 239000005557 antagonist Substances 0.000 description 21
- 230000007423 decrease Effects 0.000 description 21
- 230000006870 function Effects 0.000 description 21
- 238000011813 knockout mouse model Methods 0.000 description 21
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 21
- 238000004422 calculation algorithm Methods 0.000 description 20
- 102000004887 Transforming Growth Factor beta Human genes 0.000 description 19
- 108090001012 Transforming Growth Factor beta Proteins 0.000 description 19
- 238000012216 screening Methods 0.000 description 19
- 102100026818 Inhibin beta E chain Human genes 0.000 description 18
- 241000700605 Viruses Species 0.000 description 18
- 238000009825 accumulation Methods 0.000 description 18
- 230000009471 action Effects 0.000 description 18
- 239000003446 ligand Substances 0.000 description 18
- 238000013518 transcription Methods 0.000 description 18
- 230000035897 transcription Effects 0.000 description 18
- 239000002299 complementary DNA Substances 0.000 description 17
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 17
- 241000699666 Mus <mouse, genus> Species 0.000 description 16
- 238000004458 analytical method Methods 0.000 description 16
- 230000037396 body weight Effects 0.000 description 16
- 210000002027 skeletal muscle Anatomy 0.000 description 16
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 16
- 239000013603 viral vector Substances 0.000 description 16
- 238000003776 cleavage reaction Methods 0.000 description 15
- 239000013612 plasmid Substances 0.000 description 15
- 230000007017 scission Effects 0.000 description 15
- 238000009396 hybridization Methods 0.000 description 14
- 230000006337 proteolytic cleavage Effects 0.000 description 14
- 230000002829 reductive effect Effects 0.000 description 14
- 206010006895 Cachexia Diseases 0.000 description 13
- 230000001939 inductive effect Effects 0.000 description 13
- 230000003834 intracellular effect Effects 0.000 description 13
- 239000008194 pharmaceutical composition Substances 0.000 description 13
- 230000001413 cellular effect Effects 0.000 description 12
- 210000000349 chromosome Anatomy 0.000 description 12
- 150000001875 compounds Chemical class 0.000 description 12
- 230000000875 corresponding effect Effects 0.000 description 12
- 239000000539 dimer Substances 0.000 description 12
- 238000001727 in vivo Methods 0.000 description 12
- 238000010367 cloning Methods 0.000 description 11
- 230000018109 developmental process Effects 0.000 description 11
- 230000002068 genetic effect Effects 0.000 description 11
- 239000002502 liposome Substances 0.000 description 11
- 230000007170 pathology Effects 0.000 description 11
- 238000003752 polymerase chain reaction Methods 0.000 description 11
- 210000002966 serum Anatomy 0.000 description 11
- 230000007781 signaling event Effects 0.000 description 11
- 238000013519 translation Methods 0.000 description 11
- 230000014616 translation Effects 0.000 description 11
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 10
- 206010028980 Neoplasm Diseases 0.000 description 10
- 102000043168 TGF-beta family Human genes 0.000 description 10
- 108091085018 TGF-beta family Proteins 0.000 description 10
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 10
- 239000000556 agonist Substances 0.000 description 10
- 230000003247 decreasing effect Effects 0.000 description 10
- 210000001671 embryonic stem cell Anatomy 0.000 description 10
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 10
- 230000009870 specific binding Effects 0.000 description 10
- 101800001415 Bri23 peptide Proteins 0.000 description 9
- 101800000655 C-terminal peptide Proteins 0.000 description 9
- 102400000107 C-terminal peptide Human genes 0.000 description 9
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 9
- 241000699660 Mus musculus Species 0.000 description 9
- 239000000427 antigen Substances 0.000 description 9
- 108091007433 antigens Proteins 0.000 description 9
- 102000036639 antigens Human genes 0.000 description 9
- 239000011230 binding agent Substances 0.000 description 9
- 238000013500 data storage Methods 0.000 description 9
- 239000008103 glucose Substances 0.000 description 9
- 210000004408 hybridoma Anatomy 0.000 description 9
- 239000002609 medium Substances 0.000 description 9
- 238000000520 microinjection Methods 0.000 description 9
- 230000008569 process Effects 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- 239000000523 sample Substances 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
- 238000011282 treatment Methods 0.000 description 9
- 108090000994 Catalytic RNA Proteins 0.000 description 8
- 102000053642 Catalytic RNA Human genes 0.000 description 8
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 8
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 8
- 108091034117 Oligonucleotide Proteins 0.000 description 8
- 102000035195 Peptidases Human genes 0.000 description 8
- 108091005804 Peptidases Proteins 0.000 description 8
- 239000004365 Protease Substances 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 8
- 239000003153 chemical reaction reagent Substances 0.000 description 8
- 201000010099 disease Diseases 0.000 description 8
- 238000005516 engineering process Methods 0.000 description 8
- 239000011159 matrix material Substances 0.000 description 8
- 238000000302 molecular modelling Methods 0.000 description 8
- 230000001177 retroviral effect Effects 0.000 description 8
- 108091092562 ribozyme Proteins 0.000 description 8
- 241000701161 unidentified adenovirus Species 0.000 description 8
- 241001430294 unidentified retrovirus Species 0.000 description 8
- 208000030507 AIDS Diseases 0.000 description 7
- 241000238366 Cephalopoda Species 0.000 description 7
- 108091026890 Coding region Proteins 0.000 description 7
- 102000053602 DNA Human genes 0.000 description 7
- 206010028289 Muscle atrophy Diseases 0.000 description 7
- 238000003556 assay Methods 0.000 description 7
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 7
- 208000035475 disorder Diseases 0.000 description 7
- 231100000673 dose–response relationship Toxicity 0.000 description 7
- 210000002257 embryonic structure Anatomy 0.000 description 7
- 208000015181 infectious disease Diseases 0.000 description 7
- 239000000463 material Substances 0.000 description 7
- 230000001404 mediated effect Effects 0.000 description 7
- 108020004999 messenger RNA Proteins 0.000 description 7
- 230000004060 metabolic process Effects 0.000 description 7
- 230000037257 muscle growth Effects 0.000 description 7
- 230000026731 phosphorylation Effects 0.000 description 7
- 238000006366 phosphorylation reaction Methods 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- 230000004044 response Effects 0.000 description 7
- 238000003860 storage Methods 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 102100025748 Mothers against decapentaplegic homolog 3 Human genes 0.000 description 6
- 101710143111 Mothers against decapentaplegic homolog 3 Proteins 0.000 description 6
- 241000238367 Mya arenaria Species 0.000 description 6
- 241000700159 Rattus Species 0.000 description 6
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 6
- 241000700618 Vaccinia virus Species 0.000 description 6
- 201000011510 cancer Diseases 0.000 description 6
- 210000000170 cell membrane Anatomy 0.000 description 6
- 150000005829 chemical entities Chemical class 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 238000004590 computer program Methods 0.000 description 6
- 238000012217 deletion Methods 0.000 description 6
- 230000037430 deletion Effects 0.000 description 6
- 230000001419 dependent effect Effects 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 239000003112 inhibitor Substances 0.000 description 6
- 238000003780 insertion Methods 0.000 description 6
- 230000037431 insertion Effects 0.000 description 6
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 6
- 201000000585 muscular atrophy Diseases 0.000 description 6
- 210000000056 organ Anatomy 0.000 description 6
- 239000000816 peptidomimetic Substances 0.000 description 6
- 239000002243 precursor Substances 0.000 description 6
- 230000010076 replication Effects 0.000 description 6
- 230000003362 replicative effect Effects 0.000 description 6
- 238000011830 transgenic mouse model Methods 0.000 description 6
- 230000003612 virological effect Effects 0.000 description 6
- -1 Act RIIA Proteins 0.000 description 5
- 102000001893 Bone Morphogenetic Protein Receptors Human genes 0.000 description 5
- 108010040422 Bone Morphogenetic Protein Receptors Proteins 0.000 description 5
- 108010047041 Complementarity Determining Regions Proteins 0.000 description 5
- 241000725303 Human immunodeficiency virus Species 0.000 description 5
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 5
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 5
- 102000004877 Insulin Human genes 0.000 description 5
- 108090001061 Insulin Proteins 0.000 description 5
- 102000016267 Leptin Human genes 0.000 description 5
- 108010092277 Leptin Proteins 0.000 description 5
- 102100025751 Mothers against decapentaplegic homolog 2 Human genes 0.000 description 5
- 101710143123 Mothers against decapentaplegic homolog 2 Proteins 0.000 description 5
- 102100030608 Mothers against decapentaplegic homolog 7 Human genes 0.000 description 5
- 108020004511 Recombinant DNA Proteins 0.000 description 5
- 101700026522 SMAD7 Proteins 0.000 description 5
- 241000282887 Suidae Species 0.000 description 5
- 108020004440 Thymidine kinase Proteins 0.000 description 5
- 150000007513 acids Chemical class 0.000 description 5
- 230000008901 benefit Effects 0.000 description 5
- 230000001186 cumulative effect Effects 0.000 description 5
- 239000003937 drug carrier Substances 0.000 description 5
- 230000002255 enzymatic effect Effects 0.000 description 5
- 210000003527 eukaryotic cell Anatomy 0.000 description 5
- 210000002468 fat body Anatomy 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 230000002163 immunogen Effects 0.000 description 5
- 238000001802 infusion Methods 0.000 description 5
- 229940125396 insulin Drugs 0.000 description 5
- NRYBAZVQPHGZNS-ZSOCWYAHSA-N leptin Chemical compound O=C([C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)CC(C)C)CCSC)N1CCC[C@H]1C(=O)NCC(=O)N[C@@H](CS)C(O)=O NRYBAZVQPHGZNS-ZSOCWYAHSA-N 0.000 description 5
- 229940039781 leptin Drugs 0.000 description 5
- 231100000518 lethal Toxicity 0.000 description 5
- 230000001665 lethal effect Effects 0.000 description 5
- 210000004962 mammalian cell Anatomy 0.000 description 5
- 208000030159 metabolic disease Diseases 0.000 description 5
- 230000037361 pathway Effects 0.000 description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 5
- 230000017854 proteolysis Effects 0.000 description 5
- 238000011160 research Methods 0.000 description 5
- 239000007790 solid phase Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 238000006467 substitution reaction Methods 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 5
- 238000010361 transduction Methods 0.000 description 5
- 230000026683 transduction Effects 0.000 description 5
- 238000001890 transfection Methods 0.000 description 5
- 238000012546 transfer Methods 0.000 description 5
- 238000003160 two-hybrid assay Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 4
- 208000017667 Chronic Disease Diseases 0.000 description 4
- 102100040897 Embryonic growth/differentiation factor 1 Human genes 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 4
- 108010090296 Growth Differentiation Factor 1 Proteins 0.000 description 4
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 4
- 241000238631 Hexapoda Species 0.000 description 4
- 241000282412 Homo Species 0.000 description 4
- 108060003951 Immunoglobulin Proteins 0.000 description 4
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 4
- 102000003792 Metallothionein Human genes 0.000 description 4
- 108090000157 Metallothionein Proteins 0.000 description 4
- 102100030590 Mothers against decapentaplegic homolog 6 Human genes 0.000 description 4
- 101710143114 Mothers against decapentaplegic homolog 6 Proteins 0.000 description 4
- 241000283973 Oryctolagus cuniculus Species 0.000 description 4
- 206010038997 Retroviral infections Diseases 0.000 description 4
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 4
- 108091005735 TGF-beta receptors Proteins 0.000 description 4
- 108010022394 Threonine synthase Proteins 0.000 description 4
- 102000006601 Thymidine Kinase Human genes 0.000 description 4
- 102000016715 Transforming Growth Factor beta Receptors Human genes 0.000 description 4
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 4
- 239000013543 active substance Substances 0.000 description 4
- 238000001042 affinity chromatography Methods 0.000 description 4
- 239000000969 carrier Substances 0.000 description 4
- 230000015556 catabolic process Effects 0.000 description 4
- 230000000295 complement effect Effects 0.000 description 4
- 238000007796 conventional method Methods 0.000 description 4
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 4
- 238000006731 degradation reaction Methods 0.000 description 4
- 102000004419 dihydrofolate reductase Human genes 0.000 description 4
- 238000004520 electroporation Methods 0.000 description 4
- 229940088598 enzyme Drugs 0.000 description 4
- 235000013922 glutamic acid Nutrition 0.000 description 4
- 239000004220 glutamic acid Substances 0.000 description 4
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 4
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 4
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 4
- 229960002897 heparin Drugs 0.000 description 4
- 229920000669 heparin Polymers 0.000 description 4
- 102000018358 immunoglobulin Human genes 0.000 description 4
- 230000001976 improved effect Effects 0.000 description 4
- 230000010354 integration Effects 0.000 description 4
- 230000004807 localization Effects 0.000 description 4
- 239000003550 marker Substances 0.000 description 4
- 230000007246 mechanism Effects 0.000 description 4
- 239000012528 membrane Substances 0.000 description 4
- 230000003278 mimic effect Effects 0.000 description 4
- 238000012900 molecular simulation Methods 0.000 description 4
- 201000006938 muscular dystrophy Diseases 0.000 description 4
- 229920000642 polymer Polymers 0.000 description 4
- 235000019419 proteases Nutrition 0.000 description 4
- 239000002464 receptor antagonist Substances 0.000 description 4
- 229940044551 receptor antagonist Drugs 0.000 description 4
- 239000011435 rock Substances 0.000 description 4
- 241000701447 unidentified baculovirus Species 0.000 description 4
- 239000004474 valine Substances 0.000 description 4
- 208000016261 weight loss Diseases 0.000 description 4
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 3
- 108700028369 Alleles Proteins 0.000 description 3
- 239000004475 Arginine Substances 0.000 description 3
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 3
- 108010049955 Bone Morphogenetic Protein 4 Proteins 0.000 description 3
- 102100024505 Bone morphogenetic protein 4 Human genes 0.000 description 3
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 3
- 241000701822 Bovine papillomavirus Species 0.000 description 3
- 241000938605 Crocodylia Species 0.000 description 3
- 241000702421 Dependoparvovirus Species 0.000 description 3
- 241000588724 Escherichia coli Species 0.000 description 3
- 235000011201 Ginkgo Nutrition 0.000 description 3
- 244000194101 Ginkgo biloba Species 0.000 description 3
- 235000008100 Ginkgo biloba Nutrition 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 3
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 3
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 3
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 3
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 3
- 239000004472 Lysine Substances 0.000 description 3
- 241000829100 Macaca mulatta polyomavirus 1 Species 0.000 description 3
- 102100025725 Mothers against decapentaplegic homolog 4 Human genes 0.000 description 3
- 101710143112 Mothers against decapentaplegic homolog 4 Proteins 0.000 description 3
- 241000238413 Octopus Species 0.000 description 3
- 108020005187 Oligonucleotide Probes Proteins 0.000 description 3
- 206010033307 Overweight Diseases 0.000 description 3
- 102000057297 Pepsin A Human genes 0.000 description 3
- 108090000284 Pepsin A Proteins 0.000 description 3
- 108010043958 Peptoids Proteins 0.000 description 3
- 206010035226 Plasma cell myeloma Diseases 0.000 description 3
- 229920002684 Sepharose Polymers 0.000 description 3
- 239000004098 Tetracycline Substances 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 210000001789 adipocyte Anatomy 0.000 description 3
- 230000032683 aging Effects 0.000 description 3
- 210000004102 animal cell Anatomy 0.000 description 3
- 238000010171 animal model Methods 0.000 description 3
- 239000002246 antineoplastic agent Substances 0.000 description 3
- 238000013459 approach Methods 0.000 description 3
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 3
- 235000009582 asparagine Nutrition 0.000 description 3
- 229960001230 asparagine Drugs 0.000 description 3
- 235000003704 aspartic acid Nutrition 0.000 description 3
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 3
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- 230000033228 biological regulation Effects 0.000 description 3
- 210000001109 blastomere Anatomy 0.000 description 3
- 238000004113 cell culture Methods 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 230000008878 coupling Effects 0.000 description 3
- 238000010168 coupling process Methods 0.000 description 3
- 238000005859 coupling reaction Methods 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 238000013461 design Methods 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 238000010494 dissociation reaction Methods 0.000 description 3
- 230000005593 dissociations Effects 0.000 description 3
- 230000013020 embryo development Effects 0.000 description 3
- 238000007446 glucose tolerance test Methods 0.000 description 3
- 239000001963 growth medium Substances 0.000 description 3
- 238000011065 in-situ storage Methods 0.000 description 3
- 230000004941 influx Effects 0.000 description 3
- 239000000893 inhibin Substances 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- ZPNFWUPYTFPOJU-LPYSRVMUSA-N iniprol Chemical compound C([C@H]1C(=O)NCC(=O)NCC(=O)N[C@H]2CSSC[C@H]3C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@H](C(N[C@H](C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC=4C=CC=CC=4)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC=4C=CC=CC=4)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC2=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H]2N(CCC2)C(=O)[C@@H](N)CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N2[C@@H](CCC2)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N2[C@@H](CCC2)C(=O)N3)C(=O)NCC(=O)NCC(=O)N[C@@H](C)C(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H](C(=O)N1)C(C)C)[C@@H](C)O)[C@@H](C)CC)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 ZPNFWUPYTFPOJU-LPYSRVMUSA-N 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 3
- 229960000310 isoleucine Drugs 0.000 description 3
- 150000002632 lipids Chemical class 0.000 description 3
- 230000007762 localization of cell Effects 0.000 description 3
- 230000037323 metabolic rate Effects 0.000 description 3
- 229930182817 methionine Natural products 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 201000000050 myeloid neoplasm Diseases 0.000 description 3
- 210000000107 myocyte Anatomy 0.000 description 3
- 210000000653 nervous system Anatomy 0.000 description 3
- 208000018360 neuromuscular disease Diseases 0.000 description 3
- 238000011580 nude mouse model Methods 0.000 description 3
- 238000013116 obese mouse model Methods 0.000 description 3
- 239000002751 oligonucleotide probe Substances 0.000 description 3
- 210000002976 pectoralis muscle Anatomy 0.000 description 3
- 229940111202 pepsin Drugs 0.000 description 3
- 238000010647 peptide synthesis reaction Methods 0.000 description 3
- 230000004962 physiological condition Effects 0.000 description 3
- 239000013600 plasmid vector Substances 0.000 description 3
- XOJVVFBFDXDTEG-UHFFFAOYSA-N pristane Chemical compound CC(C)CCCC(C)CCCC(C)CCCC(C)C XOJVVFBFDXDTEG-UHFFFAOYSA-N 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000000018 receptor agonist Substances 0.000 description 3
- 229940044601 receptor agonist Drugs 0.000 description 3
- 238000012552 review Methods 0.000 description 3
- 238000007423 screening assay Methods 0.000 description 3
- 230000028327 secretion Effects 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 210000001082 somatic cell Anatomy 0.000 description 3
- 210000000952 spleen Anatomy 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 208000011580 syndromic disease Diseases 0.000 description 3
- 230000009885 systemic effect Effects 0.000 description 3
- 229960002180 tetracycline Drugs 0.000 description 3
- 229930101283 tetracycline Natural products 0.000 description 3
- 235000019364 tetracycline Nutrition 0.000 description 3
- 150000003522 tetracyclines Chemical class 0.000 description 3
- 229940124597 therapeutic agent Drugs 0.000 description 3
- 241001529453 unidentified herpesvirus Species 0.000 description 3
- 230000004580 weight loss Effects 0.000 description 3
- 238000001262 western blot Methods 0.000 description 3
- DIGQNXIGRZPYDK-WKSCXVIASA-N (2R)-6-amino-2-[[2-[[(2S)-2-[[2-[[(2R)-2-[[(2S)-2-[[(2R,3S)-2-[[2-[[(2S)-2-[[2-[[(2S)-2-[[(2S)-2-[[(2R)-2-[[(2S,3S)-2-[[(2R)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S)-2-[[(2R)-2-[[2-[[2-[[2-[(2-amino-1-hydroxyethylidene)amino]-3-carboxy-1-hydroxypropylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1-hydroxyethylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1,3-dihydroxypropylidene]amino]-1-hydroxyethylidene]amino]-1-hydroxypropylidene]amino]-1,3-dihydroxypropylidene]amino]-1,3-dihydroxypropylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1,3-dihydroxybutylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1-hydroxypropylidene]amino]-1,3-dihydroxypropylidene]amino]-1-hydroxyethylidene]amino]-1,5-dihydroxy-5-iminopentylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1,3-dihydroxybutylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1,3-dihydroxypropylidene]amino]-1-hydroxyethylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1-hydroxyethylidene]amino]hexanoic acid Chemical compound C[C@@H]([C@@H](C(=N[C@@H](CS)C(=N[C@@H](C)C(=N[C@@H](CO)C(=NCC(=N[C@@H](CCC(=N)O)C(=NC(CS)C(=N[C@H]([C@H](C)O)C(=N[C@H](CS)C(=N[C@H](CO)C(=NCC(=N[C@H](CS)C(=NCC(=N[C@H](CCCCN)C(=O)O)O)O)O)O)O)O)O)O)O)O)O)O)O)N=C([C@H](CS)N=C([C@H](CO)N=C([C@H](CO)N=C([C@H](C)N=C(CN=C([C@H](CO)N=C([C@H](CS)N=C(CN=C(C(CS)N=C(C(CC(=O)O)N=C(CN)O)O)O)O)O)O)O)O)O)O)O)O DIGQNXIGRZPYDK-WKSCXVIASA-N 0.000 description 2
- FXYZDFSNBBOHTA-UHFFFAOYSA-N 2-[amino(morpholin-4-ium-4-ylidene)methyl]guanidine;chloride Chemical compound Cl.NC(N)=NC(=N)N1CCOCC1 FXYZDFSNBBOHTA-UHFFFAOYSA-N 0.000 description 2
- 229930024421 Adenine Natural products 0.000 description 2
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 2
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 201000001320 Atherosclerosis Diseases 0.000 description 2
- 102100026189 Beta-galactosidase Human genes 0.000 description 2
- 230000005724 C-terminal phosphorylation Effects 0.000 description 2
- 241000283707 Capra Species 0.000 description 2
- 108010035563 Chloramphenicol O-acetyltransferase Proteins 0.000 description 2
- 241000251556 Chordata Species 0.000 description 2
- 244000072510 Claytonia virginica Species 0.000 description 2
- 241000699800 Cricetinae Species 0.000 description 2
- 241000238424 Crustacea Species 0.000 description 2
- 241000701022 Cytomegalovirus Species 0.000 description 2
- 150000008574 D-amino acids Chemical class 0.000 description 2
- 229920002307 Dextran Polymers 0.000 description 2
- 241000258955 Echinodermata Species 0.000 description 2
- 241000206602 Eukaryota Species 0.000 description 2
- 108700028146 Genetic Enhancer Elements Proteins 0.000 description 2
- 206010018429 Glucose tolerance impaired Diseases 0.000 description 2
- 108010024636 Glutathione Proteins 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 241000238071 Homarus americanus Species 0.000 description 2
- 101000886562 Homo sapiens Growth/differentiation factor 8 Proteins 0.000 description 2
- 206010020772 Hypertension Diseases 0.000 description 2
- 206010020880 Hypertrophy Diseases 0.000 description 2
- 206010065042 Immune reconstitution inflammatory syndrome Diseases 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 description 2
- 102000004218 Insulin-Like Growth Factor I Human genes 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- 108010025815 Kanamycin Kinase Proteins 0.000 description 2
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 2
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 2
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 2
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 2
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 2
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 2
- 108060001084 Luciferase Proteins 0.000 description 2
- 241001599018 Melanogaster Species 0.000 description 2
- 241000237852 Mollusca Species 0.000 description 2
- 206010028311 Muscle hypertrophy Diseases 0.000 description 2
- 241000097679 Myzomela rosenbergii Species 0.000 description 2
- 230000004988 N-glycosylation Effects 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 102000052812 Ornithine decarboxylases Human genes 0.000 description 2
- 108700005126 Ornithine decarboxylases Proteins 0.000 description 2
- 108010033276 Peptide Fragments Proteins 0.000 description 2
- 102000007079 Peptide Fragments Human genes 0.000 description 2
- 241000286209 Phasianidae Species 0.000 description 2
- 102000001253 Protein Kinase Human genes 0.000 description 2
- 101710149951 Protein Tat Proteins 0.000 description 2
- 244000086363 Pterocarpus indicus Species 0.000 description 2
- 108091005682 Receptor kinases Proteins 0.000 description 2
- 108091028664 Ribonucleotide Proteins 0.000 description 2
- 241001125048 Sardina Species 0.000 description 2
- 238000012300 Sequence Analysis Methods 0.000 description 2
- 108020004682 Single-Stranded DNA Proteins 0.000 description 2
- 108010007945 Smad Proteins Proteins 0.000 description 2
- 102000007374 Smad Proteins Human genes 0.000 description 2
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 2
- 239000004473 Threonine Substances 0.000 description 2
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 2
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 241000863480 Vinca Species 0.000 description 2
- 208000010399 Wasting Syndrome Diseases 0.000 description 2
- 208000027418 Wounds and injury Diseases 0.000 description 2
- 241000269370 Xenopus <genus> Species 0.000 description 2
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 2
- 229960000643 adenine Drugs 0.000 description 2
- 230000011759 adipose tissue development Effects 0.000 description 2
- 230000003321 amplification Effects 0.000 description 2
- 230000001195 anabolic effect Effects 0.000 description 2
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 2
- 208000022531 anorexia Diseases 0.000 description 2
- 230000003302 anti-idiotype Effects 0.000 description 2
- 229940041181 antineoplastic drug Drugs 0.000 description 2
- 238000002869 basic local alignment search tool Methods 0.000 description 2
- 108010005774 beta-Galactosidase Proteins 0.000 description 2
- 230000001588 bifunctional effect Effects 0.000 description 2
- 230000000975 bioactive effect Effects 0.000 description 2
- 238000004166 bioassay Methods 0.000 description 2
- 239000011616 biotin Substances 0.000 description 2
- 229960002685 biotin Drugs 0.000 description 2
- 235000020958 biotin Nutrition 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 230000006583 body weight regulation Effects 0.000 description 2
- 229940098773 bovine serum albumin Drugs 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- 229910000389 calcium phosphate Inorganic materials 0.000 description 2
- 235000011010 calcium phosphates Nutrition 0.000 description 2
- 150000001720 carbohydrates Chemical class 0.000 description 2
- 235000014633 carbohydrates Nutrition 0.000 description 2
- 230000022159 cartilage development Effects 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 230000032823 cell division Effects 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 239000013599 cloning vector Substances 0.000 description 2
- 238000012761 co-transfection Methods 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 230000000536 complexating effect Effects 0.000 description 2
- DDRJAANPRJIHGJ-UHFFFAOYSA-N creatinine Chemical compound CN1CC(=O)NC1=N DDRJAANPRJIHGJ-UHFFFAOYSA-N 0.000 description 2
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 2
- 229940104302 cytosine Drugs 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 206010061428 decreased appetite Diseases 0.000 description 2
- 239000005547 deoxyribonucleotide Substances 0.000 description 2
- 125000002637 deoxyribonucleotide group Chemical group 0.000 description 2
- 230000030609 dephosphorylation Effects 0.000 description 2
- 238000006209 dephosphorylation reaction Methods 0.000 description 2
- 238000009510 drug design Methods 0.000 description 2
- VLCYCQAOQCDTCN-UHFFFAOYSA-N eflornithine Chemical compound NCCCC(N)(C(F)F)C(O)=O VLCYCQAOQCDTCN-UHFFFAOYSA-N 0.000 description 2
- 238000001962 electrophoresis Methods 0.000 description 2
- 210000002308 embryonic cell Anatomy 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 230000001605 fetal effect Effects 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 230000004927 fusion Effects 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 238000001502 gel electrophoresis Methods 0.000 description 2
- 238000002523 gelfiltration Methods 0.000 description 2
- 238000003209 gene knockout Methods 0.000 description 2
- 229960003180 glutathione Drugs 0.000 description 2
- 230000013595 glycosylation Effects 0.000 description 2
- 238000006206 glycosylation reaction Methods 0.000 description 2
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 2
- 229910052737 gold Inorganic materials 0.000 description 2
- 239000010931 gold Substances 0.000 description 2
- 239000003102 growth factor Substances 0.000 description 2
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 2
- 125000001165 hydrophobic group Chemical group 0.000 description 2
- 206010020718 hyperplasia Diseases 0.000 description 2
- 229940027941 immunoglobulin g Drugs 0.000 description 2
- 208000014674 injury Diseases 0.000 description 2
- 210000001596 intra-abdominal fat Anatomy 0.000 description 2
- 238000010255 intramuscular injection Methods 0.000 description 2
- 239000007927 intramuscular injection Substances 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 238000010253 intravenous injection Methods 0.000 description 2
- 238000004255 ion exchange chromatography Methods 0.000 description 2
- 108010045069 keyhole-limpet hemocyanin Proteins 0.000 description 2
- 238000002372 labelling Methods 0.000 description 2
- 108010034897 lentil lectin Proteins 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 229960000485 methotrexate Drugs 0.000 description 2
- 239000000693 micelle Substances 0.000 description 2
- 239000004530 micro-emulsion Substances 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 230000012042 muscle hypertrophy Effects 0.000 description 2
- 238000002703 mutagenesis Methods 0.000 description 2
- 231100000350 mutagenesis Toxicity 0.000 description 2
- 208000010125 myocardial infarction Diseases 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 238000003199 nucleic acid amplification method Methods 0.000 description 2
- 238000007899 nucleic acid hybridization Methods 0.000 description 2
- 210000004940 nucleus Anatomy 0.000 description 2
- 235000015097 nutrients Nutrition 0.000 description 2
- 235000016709 nutrition Nutrition 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 230000002018 overexpression Effects 0.000 description 2
- 238000004806 packaging method and process Methods 0.000 description 2
- 238000002823 phage display Methods 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 2
- 150000004713 phosphodiesters Chemical class 0.000 description 2
- 230000008488 polyadenylation Effects 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 108060006633 protein kinase Proteins 0.000 description 2
- 238000001742 protein purification Methods 0.000 description 2
- 238000003259 recombinant expression Methods 0.000 description 2
- 230000006798 recombination Effects 0.000 description 2
- 238000005215 recombination Methods 0.000 description 2
- 230000002441 reversible effect Effects 0.000 description 2
- 239000002336 ribonucleotide Substances 0.000 description 2
- 125000002652 ribonucleotide group Chemical group 0.000 description 2
- 238000012163 sequencing technique Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 210000004988 splenocyte Anatomy 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 230000010473 stable expression Effects 0.000 description 2
- 210000000130 stem cell Anatomy 0.000 description 2
- 230000004936 stimulating effect Effects 0.000 description 2
- 238000010254 subcutaneous injection Methods 0.000 description 2
- 239000007929 subcutaneous injection Substances 0.000 description 2
- 239000013589 supplement Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 230000008685 targeting Effects 0.000 description 2
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical compound CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 description 2
- 210000001541 thymus gland Anatomy 0.000 description 2
- 230000009772 tissue formation Effects 0.000 description 2
- 230000008467 tissue growth Effects 0.000 description 2
- 238000002627 tracheal intubation Methods 0.000 description 2
- 238000003151 transfection method Methods 0.000 description 2
- 230000005945 translocation Effects 0.000 description 2
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 2
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 2
- 241001515965 unidentified phage Species 0.000 description 2
- 210000004291 uterus Anatomy 0.000 description 2
- 229910052720 vanadium Inorganic materials 0.000 description 2
- 210000005253 yeast cell Anatomy 0.000 description 2
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 1
- BFSVOASYOCHEOV-UHFFFAOYSA-N 2-diethylaminoethanol Chemical compound CCN(CC)CCO BFSVOASYOCHEOV-UHFFFAOYSA-N 0.000 description 1
- HVCOBJNICQPDBP-UHFFFAOYSA-N 3-[3-[3,5-dihydroxy-6-methyl-4-(3,4,5-trihydroxy-6-methyloxan-2-yl)oxyoxan-2-yl]oxydecanoyloxy]decanoic acid;hydrate Chemical compound O.OC1C(OC(CC(=O)OC(CCCCCCC)CC(O)=O)CCCCCCC)OC(C)C(O)C1OC1C(O)C(O)C(O)C(C)O1 HVCOBJNICQPDBP-UHFFFAOYSA-N 0.000 description 1
- IRLPACMLTUPBCL-KQYNXXCUSA-N 5'-adenylyl sulfate Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OS(O)(=O)=O)[C@@H](O)[C@H]1O IRLPACMLTUPBCL-KQYNXXCUSA-N 0.000 description 1
- 101710169336 5'-deoxyadenosine deaminase Proteins 0.000 description 1
- 101150094949 APRT gene Proteins 0.000 description 1
- 108010085238 Actins Proteins 0.000 description 1
- 102000007469 Actins Human genes 0.000 description 1
- 102100029457 Adenine phosphoribosyltransferase Human genes 0.000 description 1
- 108010024223 Adenine phosphoribosyltransferase Proteins 0.000 description 1
- 102100036664 Adenosine deaminase Human genes 0.000 description 1
- 229920000936 Agarose Polymers 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 108020000948 Antisense Oligonucleotides Proteins 0.000 description 1
- 108020005544 Antisense RNA Proteins 0.000 description 1
- 241000269350 Anura Species 0.000 description 1
- 241000219194 Arabidopsis Species 0.000 description 1
- OMLWNBVRVJYMBQ-YUMQZZPRSA-N Arg-Arg Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O OMLWNBVRVJYMBQ-YUMQZZPRSA-N 0.000 description 1
- QYLJIYOGHRGUIH-CIUDSAMLSA-N Arg-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@@H](N)CCCNC(N)=N QYLJIYOGHRGUIH-CIUDSAMLSA-N 0.000 description 1
- 208000002109 Argyria Diseases 0.000 description 1
- 241000714230 Avian leukemia virus Species 0.000 description 1
- 108090001008 Avidin Proteins 0.000 description 1
- 108010049931 Bone Morphogenetic Protein 2 Proteins 0.000 description 1
- 108010049951 Bone Morphogenetic Protein 3 Proteins 0.000 description 1
- 102100024506 Bone morphogenetic protein 2 Human genes 0.000 description 1
- 102100024504 Bone morphogenetic protein 3 Human genes 0.000 description 1
- 241000238097 Callinectes sapidus Species 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 102000014914 Carrier Proteins Human genes 0.000 description 1
- 108010078791 Carrier Proteins Proteins 0.000 description 1
- 241000701489 Cauliflower mosaic virus Species 0.000 description 1
- 102000000844 Cell Surface Receptors Human genes 0.000 description 1
- 108010001857 Cell Surface Receptors Proteins 0.000 description 1
- 241001529572 Chaceon affinis Species 0.000 description 1
- 229940123150 Chelating agent Drugs 0.000 description 1
- 108020004705 Codon Proteins 0.000 description 1
- 108010071942 Colony-Stimulating Factors Proteins 0.000 description 1
- 108020004635 Complementary DNA Proteins 0.000 description 1
- 206010010356 Congenital anomaly Diseases 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 241001274613 Corvus frugilegus Species 0.000 description 1
- 241000548230 Crassostrea angulata Species 0.000 description 1
- 241000699802 Cricetulus griseus Species 0.000 description 1
- 241000229668 Crocodylus acutus Species 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 description 1
- 101150074155 DHFR gene Proteins 0.000 description 1
- 230000006820 DNA synthesis Effects 0.000 description 1
- 241000723298 Dicentrarchus labrax Species 0.000 description 1
- 108090000204 Dipeptidase 1 Proteins 0.000 description 1
- 108700003483 Drosophila dpp Proteins 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 241000237537 Ensis Species 0.000 description 1
- YQYJSBFKSSDGFO-UHFFFAOYSA-N Epihygromycin Natural products OC1C(O)C(C(=O)C)OC1OC(C(=C1)O)=CC=C1C=C(C)C(=O)NC1C(O)C(O)C2OCOC2C1O YQYJSBFKSSDGFO-UHFFFAOYSA-N 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 102000003951 Erythropoietin Human genes 0.000 description 1
- 108090000394 Erythropoietin Proteins 0.000 description 1
- 101001091269 Escherichia coli Hygromycin-B 4-O-kinase Proteins 0.000 description 1
- 241000701959 Escherichia virus Lambda Species 0.000 description 1
- 108010008177 Fd immunoglobulins Proteins 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 241000767091 Gaidropsarus ensis Species 0.000 description 1
- 101001035782 Gallus gallus Hemoglobin subunit beta Proteins 0.000 description 1
- 101000824878 Gallus gallus Somatotropin Proteins 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- SXRSQZLOMIGNAQ-UHFFFAOYSA-N Glutaraldehyde Chemical compound O=CCCCC=O SXRSQZLOMIGNAQ-UHFFFAOYSA-N 0.000 description 1
- 102000005720 Glutathione transferase Human genes 0.000 description 1
- 108010070675 Glutathione transferase Proteins 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 229930186217 Glycolipid Natural products 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 description 1
- 108010043121 Green Fluorescent Proteins Proteins 0.000 description 1
- 102000014015 Growth Differentiation Factors Human genes 0.000 description 1
- 108010050777 Growth Differentiation Factors Proteins 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 241000606768 Haemophilus influenzae Species 0.000 description 1
- 208000009889 Herpes Simplex Diseases 0.000 description 1
- 108010000521 Human Growth Hormone Proteins 0.000 description 1
- 101100321817 Human parvovirus B19 (strain HV) 7.5K gene Proteins 0.000 description 1
- 108010091358 Hypoxanthine Phosphoribosyltransferase Proteins 0.000 description 1
- 102100029098 Hypoxanthine-guanine phosphoribosyltransferase Human genes 0.000 description 1
- 108010091135 Immunoglobulin Fc Fragments Proteins 0.000 description 1
- 102000018071 Immunoglobulin Fc Fragments Human genes 0.000 description 1
- 108010067060 Immunoglobulin Variable Region Proteins 0.000 description 1
- 102000017727 Immunoglobulin Variable Region Human genes 0.000 description 1
- 108020004684 Internal Ribosome Entry Sites Proteins 0.000 description 1
- 108010076876 Keratins Proteins 0.000 description 1
- 102000011782 Keratins Human genes 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- 150000008575 L-amino acids Chemical class 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 241000713666 Lentivirus Species 0.000 description 1
- 108090001030 Lipoproteins Proteins 0.000 description 1
- 102000004895 Lipoproteins Human genes 0.000 description 1
- 241000368589 Lophotus lacepede Species 0.000 description 1
- 239000005089 Luciferase Substances 0.000 description 1
- NPBGTPKLVJEOBE-IUCAKERBSA-N Lys-Arg Chemical compound NCCCC[C@H](N)C(=O)N[C@H](C(O)=O)CCCNC(N)=N NPBGTPKLVJEOBE-IUCAKERBSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 241000258241 Mantis Species 0.000 description 1
- 241000203407 Methanocaldococcus jannaschii Species 0.000 description 1
- 108010021466 Mutant Proteins Proteins 0.000 description 1
- 102000008300 Mutant Proteins Human genes 0.000 description 1
- 102100038895 Myc proto-oncogene protein Human genes 0.000 description 1
- 101710135898 Myc proto-oncogene protein Proteins 0.000 description 1
- 241000204051 Mycoplasma genitalium Species 0.000 description 1
- BKAYIFDRRZZKNF-VIFPVBQESA-N N-acetylcarnosine Chemical compound CC(=O)NCCC(=O)N[C@H](C(O)=O)CC1=CN=CN1 BKAYIFDRRZZKNF-VIFPVBQESA-N 0.000 description 1
- 241000244489 Navia Species 0.000 description 1
- 241001045988 Neogene Species 0.000 description 1
- VEQPNABPJHWNSG-UHFFFAOYSA-N Nickel(2+) Chemical compound [Ni+2] VEQPNABPJHWNSG-UHFFFAOYSA-N 0.000 description 1
- 108020004485 Nonsense Codon Proteins 0.000 description 1
- 108010077850 Nuclear Localization Signals Proteins 0.000 description 1
- 208000011623 Obstructive Lung disease Diseases 0.000 description 1
- 108010038807 Oligopeptides Proteins 0.000 description 1
- 102000015636 Oligopeptides Human genes 0.000 description 1
- 102000016979 Other receptors Human genes 0.000 description 1
- 108090000526 Papain Proteins 0.000 description 1
- 241000282520 Papio Species 0.000 description 1
- 241000237509 Patinopecten sp. Species 0.000 description 1
- 101000851110 Periplaneta americana Vitellogenin-1 Proteins 0.000 description 1
- 108091000041 Phosphoenolpyruvate Carboxylase Proteins 0.000 description 1
- 108090000472 Phosphoenolpyruvate carboxykinase (ATP) Proteins 0.000 description 1
- 102100034792 Phosphoenolpyruvate carboxykinase [GTP], mitochondrial Human genes 0.000 description 1
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 1
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 1
- 101100124346 Photorhabdus laumondii subsp. laumondii (strain DSM 15139 / CIP 105565 / TT01) hisCD gene Proteins 0.000 description 1
- 241000861915 Plecoglossus Species 0.000 description 1
- 241000861914 Plecoglossus altivelis Species 0.000 description 1
- 241001600434 Plectroglyphidodon lacrymatus Species 0.000 description 1
- 241000276498 Pollachius virens Species 0.000 description 1
- 101710182846 Polyhedrin Proteins 0.000 description 1
- 241001505332 Polyomavirus sp. Species 0.000 description 1
- 241001529596 Pontinus kuhlii Species 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- 108020004518 RNA Probes Proteins 0.000 description 1
- 239000003391 RNA probe Substances 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 1
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 1
- 208000001647 Renal Insufficiency Diseases 0.000 description 1
- 108700008625 Reporter Genes Proteins 0.000 description 1
- 208000017442 Retinal disease Diseases 0.000 description 1
- 206010038923 Retinopathy Diseases 0.000 description 1
- 240000002044 Rhizophora apiculata Species 0.000 description 1
- 240000003793 Rhizophora mangle Species 0.000 description 1
- PYMYPHUHKUWMLA-LMVFSUKVSA-N Ribose Natural products OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 241000714474 Rous sarcoma virus Species 0.000 description 1
- 241000231739 Rutilus rutilus Species 0.000 description 1
- 241000235070 Saccharomyces Species 0.000 description 1
- 241000710961 Semliki Forest virus Species 0.000 description 1
- 229920005654 Sephadex Polymers 0.000 description 1
- 239000012507 Sephadex™ Substances 0.000 description 1
- 241000238371 Sepiidae Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- 241000700584 Simplexvirus Species 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 244000061458 Solanum melongena Species 0.000 description 1
- 235000002597 Solanum melongena Nutrition 0.000 description 1
- 241000727771 Solenocera melantho Species 0.000 description 1
- 238000002105 Southern blotting Methods 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 108010090804 Streptavidin Proteins 0.000 description 1
- 101001091268 Streptomyces hygroscopicus Hygromycin-B 7''-O-kinase Proteins 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 241001441724 Tetraodontidae Species 0.000 description 1
- 241000723873 Tobacco mosaic virus Species 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- 101710150448 Transcriptional regulator Myc Proteins 0.000 description 1
- 108700005077 Viral Genes Proteins 0.000 description 1
- 208000021017 Weight Gain Diseases 0.000 description 1
- 108010027570 Xanthine phosphoribosyltransferase Proteins 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 238000004847 absorption spectroscopy Methods 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000000370 acceptor Substances 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Natural products OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 102000006646 aminoglycoside phosphotransferase Human genes 0.000 description 1
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 1
- 230000019552 anatomical structure morphogenesis Effects 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000340 anti-metabolite Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 210000000628 antibody-producing cell Anatomy 0.000 description 1
- 102000025171 antigen binding proteins Human genes 0.000 description 1
- 108091000831 antigen binding proteins Proteins 0.000 description 1
- 230000000890 antigenic effect Effects 0.000 description 1
- 229940100197 antimetabolite Drugs 0.000 description 1
- 239000002256 antimetabolite Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000000074 antisense oligonucleotide Substances 0.000 description 1
- 238000012230 antisense oligonucleotides Methods 0.000 description 1
- 230000036528 appetite Effects 0.000 description 1
- 235000019789 appetite Nutrition 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000000637 arginyl group Chemical group N[C@@H](CCCNC(N)=N)C(=O)* 0.000 description 1
- 108010068380 arginylarginine Proteins 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 210000001106 artificial yeast chromosome Anatomy 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 230000002238 attenuated effect Effects 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 102000006635 beta-lactamase Human genes 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 239000003124 biologic agent Substances 0.000 description 1
- 239000003181 biological factor Substances 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 208000029162 bladder disease Diseases 0.000 description 1
- 239000002981 blocking agent Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 108010006025 bovine growth hormone Proteins 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 244000309466 calf Species 0.000 description 1
- 208000035269 cancer or benign tumor Diseases 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 210000000845 cartilage Anatomy 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 230000011712 cell development Effects 0.000 description 1
- 230000003196 chaotropic effect Effects 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 239000013043 chemical agent Substances 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 230000004186 co-expression Effects 0.000 description 1
- 229910001429 cobalt ion Inorganic materials 0.000 description 1
- XLJKHNWPARRRJB-UHFFFAOYSA-N cobalt(2+) Chemical compound [Co+2] XLJKHNWPARRRJB-UHFFFAOYSA-N 0.000 description 1
- 239000008119 colloidal silica Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 230000006957 competitive inhibition Effects 0.000 description 1
- 239000003184 complementary RNA Substances 0.000 description 1
- 239000003636 conditioned culture medium Substances 0.000 description 1
- 208000012696 congenital leptin deficiency Diseases 0.000 description 1
- 230000037011 constitutive activity Effects 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 229920001577 copolymer Chemical compound 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 229940109239 creatinine Drugs 0.000 description 1
- 239000013058 crude material Substances 0.000 description 1
- 210000004748 cultured cell Anatomy 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 239000007933 dermal patch Substances 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 238000002050 diffraction method Methods 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- RXKJFZQQPQGTFL-UHFFFAOYSA-N dihydroxyacetone Chemical compound OCC(=O)CO RXKJFZQQPQGTFL-UHFFFAOYSA-N 0.000 description 1
- GXGAKHNRMVGRPK-UHFFFAOYSA-N dimagnesium;dioxido-bis[[oxido(oxo)silyl]oxy]silane Chemical compound [Mg+2].[Mg+2].[O-][Si](=O)O[Si]([O-])([O-])O[Si]([O-])=O GXGAKHNRMVGRPK-UHFFFAOYSA-N 0.000 description 1
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 150000002019 disulfides Chemical class 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000005584 early death Effects 0.000 description 1
- 230000000081 effect on glucose Effects 0.000 description 1
- 230000009881 electrostatic interaction Effects 0.000 description 1
- 230000030583 endoplasmic reticulum localization Effects 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 238000001976 enzyme digestion Methods 0.000 description 1
- 210000000918 epididymis Anatomy 0.000 description 1
- 201000010063 epididymitis Diseases 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 230000009786 epithelial differentiation Effects 0.000 description 1
- 229940105423 erythropoietin Drugs 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 210000000416 exudates and transudate Anatomy 0.000 description 1
- 239000012894 fetal calf serum Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 238000005194 fractionation Methods 0.000 description 1
- 230000037433 frameshift Effects 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 238000002825 functional assay Methods 0.000 description 1
- 108020001507 fusion proteins Proteins 0.000 description 1
- 102000037865 fusion proteins Human genes 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 238000010353 genetic engineering Methods 0.000 description 1
- 238000012268 genome sequencing Methods 0.000 description 1
- 230000004153 glucose metabolism Effects 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 229930182470 glycoside Natural products 0.000 description 1
- 210000004013 groin Anatomy 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 235000004280 healthy diet Nutrition 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 230000011132 hemopoiesis Effects 0.000 description 1
- 239000000833 heterodimer Substances 0.000 description 1
- 239000008241 heterogeneous mixture Substances 0.000 description 1
- 101150113423 hisD gene Proteins 0.000 description 1
- 239000000710 homodimer Substances 0.000 description 1
- 238000002744 homologous recombination Methods 0.000 description 1
- 230000006801 homologous recombination Effects 0.000 description 1
- 102000054677 human MSTN Human genes 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 229910052588 hydroxylapatite Inorganic materials 0.000 description 1
- 230000000984 immunochemical effect Effects 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 230000016784 immunoglobulin production Effects 0.000 description 1
- 229940072221 immunoglobulins Drugs 0.000 description 1
- 238000001114 immunoprecipitation Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000007901 in situ hybridization Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 230000003914 insulin secretion Effects 0.000 description 1
- 102000006495 integrins Human genes 0.000 description 1
- 108010044426 integrins Proteins 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 238000001638 lipofection Methods 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 238000002865 local sequence alignment Methods 0.000 description 1
- 238000004020 luminiscence type Methods 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 230000002101 lytic effect Effects 0.000 description 1
- 238000007403 mPCR Methods 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 239000000391 magnesium silicate Substances 0.000 description 1
- 229940099273 magnesium trisilicate Drugs 0.000 description 1
- 229910000386 magnesium trisilicate Inorganic materials 0.000 description 1
- 235000019793 magnesium trisilicate Nutrition 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 238000007726 management method Methods 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 230000035800 maturation Effects 0.000 description 1
- 210000003716 mesoderm Anatomy 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- HPNSFSBZBAHARI-UHFFFAOYSA-N micophenolic acid Natural products OC1=C(CC=C(C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-UHFFFAOYSA-N 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 210000004939 midgestation embryo Anatomy 0.000 description 1
- 210000001700 mitochondrial membrane Anatomy 0.000 description 1
- 238000010369 molecular cloning Methods 0.000 description 1
- 238000000329 molecular dynamics simulation Methods 0.000 description 1
- 230000004001 molecular interaction Effects 0.000 description 1
- 238000000324 molecular mechanic Methods 0.000 description 1
- 208000001022 morbid obesity Diseases 0.000 description 1
- 210000002161 motor neuron Anatomy 0.000 description 1
- 238000002887 multiple sequence alignment Methods 0.000 description 1
- 230000020763 muscle atrophy Effects 0.000 description 1
- 230000007336 muscle tissue development Effects 0.000 description 1
- HPNSFSBZBAHARI-RUDMXATFSA-N mycophenolic acid Chemical compound OC1=C(C\C=C(/C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-RUDMXATFSA-N 0.000 description 1
- 229960000951 mycophenolic acid Drugs 0.000 description 1
- 210000003098 myoblast Anatomy 0.000 description 1
- 230000001114 myogenic effect Effects 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 230000032405 negative regulation of neuron apoptotic process Effects 0.000 description 1
- 101150091879 neo gene Proteins 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 201000001119 neuropathy Diseases 0.000 description 1
- 230000007823 neuropathy Effects 0.000 description 1
- 229910001453 nickel ion Inorganic materials 0.000 description 1
- 230000006959 non-competitive inhibition Effects 0.000 description 1
- 230000009871 nonspecific binding Effects 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 150000003833 nucleoside derivatives Chemical class 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 229920001542 oligosaccharide Polymers 0.000 description 1
- 150000002482 oligosaccharides Chemical class 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 238000010397 one-hybrid screening Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000002895 organic esters Chemical class 0.000 description 1
- 239000002818 ornithine decarboxylase inhibitor Substances 0.000 description 1
- 230000011164 ossification Effects 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000036284 oxygen consumption Effects 0.000 description 1
- HFHZKZSRXITVMK-UHFFFAOYSA-N oxyphenbutazone Chemical compound O=C1C(CCCC)C(=O)N(C=2C=CC=CC=2)N1C1=CC=C(O)C=C1 HFHZKZSRXITVMK-UHFFFAOYSA-N 0.000 description 1
- 229940055729 papain Drugs 0.000 description 1
- 235000019834 papain Nutrition 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 238000009520 phase I clinical trial Methods 0.000 description 1
- 238000009521 phase II clinical trial Methods 0.000 description 1
- 238000002135 phase contrast microscopy Methods 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- KCRZDTROFIOPBP-UHFFFAOYSA-N phosphono 2,3-dihydroxypropanoate Chemical compound OCC(O)C(=O)OP(O)(O)=O KCRZDTROFIOPBP-UHFFFAOYSA-N 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 229940012957 plasmin Drugs 0.000 description 1
- 229920002401 polyacrylamide Polymers 0.000 description 1
- 229920002704 polyhistidine Polymers 0.000 description 1
- 229920000656 polylysine Polymers 0.000 description 1
- 235000020004 porter Nutrition 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 230000004481 post-translational protein modification Effects 0.000 description 1
- 230000000291 postprandial effect Effects 0.000 description 1
- OXCMYAYHXIHQOA-UHFFFAOYSA-N potassium;[2-butyl-5-chloro-3-[[4-[2-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol Chemical compound [K+].CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C2=N[N-]N=N2)C=C1 OXCMYAYHXIHQOA-UHFFFAOYSA-N 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 210000001236 prokaryotic cell Anatomy 0.000 description 1
- 230000001902 propagating effect Effects 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 230000006916 protein interaction Effects 0.000 description 1
- 238000000734 protein sequencing Methods 0.000 description 1
- 238000000455 protein structure prediction Methods 0.000 description 1
- 230000004850 protein–protein interaction Effects 0.000 description 1
- 210000001938 protoplast Anatomy 0.000 description 1
- 238000010379 pull-down assay Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000003642 reactive oxygen metabolite Substances 0.000 description 1
- 230000010837 receptor-mediated endocytosis Effects 0.000 description 1
- 238000010188 recombinant method Methods 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 230000012865 response to insecticide Effects 0.000 description 1
- 238000002976 reverse transcriptase assay Methods 0.000 description 1
- 238000010839 reverse transcription Methods 0.000 description 1
- 125000000548 ribosyl group Chemical group C1([C@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 1
- 239000007320 rich medium Substances 0.000 description 1
- 238000010845 search algorithm Methods 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 239000006152 selective media Substances 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000002864 sequence alignment Methods 0.000 description 1
- 230000036301 sexual development Effects 0.000 description 1
- 235000015170 shellfish Nutrition 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 102000035025 signaling receptors Human genes 0.000 description 1
- 108091005475 signaling receptors Proteins 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 239000002356 single layer Substances 0.000 description 1
- 238000002741 site-directed mutagenesis Methods 0.000 description 1
- 238000001542 size-exclusion chromatography Methods 0.000 description 1
- 230000025175 skeletal muscle hypertrophy Effects 0.000 description 1
- 230000022379 skeletal muscle tissue development Effects 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 230000000392 somatic effect Effects 0.000 description 1
- 208000020431 spinal cord injury Diseases 0.000 description 1
- 230000037436 splice-site mutation Effects 0.000 description 1
- 238000012289 standard assay Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000010972 statistical evaluation Methods 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000004575 stone Substances 0.000 description 1
- 238000000547 structure data Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000002198 surface plasmon resonance spectroscopy Methods 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 238000004114 suspension culture Methods 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 229940113082 thymine Drugs 0.000 description 1
- 239000003104 tissue culture media Substances 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 108700012359 toxins Proteins 0.000 description 1
- 239000011573 trace mineral Substances 0.000 description 1
- 235000013619 trace mineral Nutrition 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- 238000011426 transformation method Methods 0.000 description 1
- 230000010474 transient expression Effects 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- 230000001228 trophic effect Effects 0.000 description 1
- 238000010396 two-hybrid screening Methods 0.000 description 1
- 230000006967 uncompetitive inhibition Effects 0.000 description 1
- 229940035893 uracil Drugs 0.000 description 1
- 208000026533 urinary bladder disease Diseases 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
- 238000012800 visualization Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 230000004584 weight gain Effects 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
- 210000004340 zona pellucida Anatomy 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K67/00—Rearing or breeding animals, not otherwise provided for; New or modified breeds of animals
- A01K67/027—New or modified breeds of vertebrates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K67/00—Rearing or breeding animals, not otherwise provided for; New or modified breeds of animals
- A01K67/027—New or modified breeds of vertebrates
- A01K67/0271—Chimeric vertebrates, e.g. comprising exogenous cells
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K67/00—Rearing or breeding animals, not otherwise provided for; New or modified breeds of animals
- A01K67/027—New or modified breeds of vertebrates
- A01K67/0275—Genetically modified vertebrates, e.g. transgenic
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K67/00—Rearing or breeding animals, not otherwise provided for; New or modified breeds of animals
- A01K67/027—New or modified breeds of vertebrates
- A01K67/0275—Genetically modified vertebrates, e.g. transgenic
- A01K67/0276—Knock-out vertebrates
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K67/00—Rearing or breeding animals, not otherwise provided for; New or modified breeds of animals
- A01K67/027—New or modified breeds of vertebrates
- A01K67/0275—Genetically modified vertebrates, e.g. transgenic
- A01K67/0278—Knock-in vertebrates, e.g. humanised vertebrates
-
- A—HUMAN NECESSITIES
- A22—BUTCHERING; MEAT TREATMENT; PROCESSING POULTRY OR FISH
- A22C—PROCESSING MEAT, POULTRY, OR FISH
- A22C18/00—Plants, factories, or the like for processing meat
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/06—Anabolic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
- C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
- C07K14/4702—Regulators; Modulating activity
- C07K14/4703—Inhibitors; Suppressors
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/475—Growth factors; Growth regulators
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
- C07K14/71—Receptors; Cell surface antigens; Cell surface determinants for growth factors; for growth regulators
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
- C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
- C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
- C12N15/8509—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells for producing genetically modified animals, e.g. transgenic
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/74—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving hormones or other non-cytokine intercellular protein regulatory factors such as growth factors, including receptors to hormones and growth factors
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2207/00—Modified animals
- A01K2207/15—Humanized animals
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2217/00—Genetically modified animals
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2217/00—Genetically modified animals
- A01K2217/05—Animals comprising random inserted nucleic acids (transgenic)
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2217/00—Genetically modified animals
- A01K2217/07—Animals genetically altered by homologous recombination
- A01K2217/075—Animals genetically altered by homologous recombination inducing loss of function, i.e. knock out
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2217/00—Genetically modified animals
- A01K2217/20—Animal model comprising regulated expression system
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2227/00—Animals characterised by species
- A01K2227/10—Mammal
- A01K2227/105—Murine
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2227/00—Animals characterised by species
- A01K2227/30—Bird
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2267/00—Animals characterised by purpose
- A01K2267/02—Animal zootechnically ameliorated
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2267/00—Animals characterised by purpose
- A01K2267/03—Animal model, e.g. for test or diseases
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2267/00—Animals characterised by purpose
- A01K2267/03—Animal model, e.g. for test or diseases
- A01K2267/0306—Animal model for genetic diseases
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2267/00—Animals characterised by purpose
- A01K2267/03—Animal model, e.g. for test or diseases
- A01K2267/035—Animal model for multifactorial diseases
- A01K2267/0362—Animal model for lipid/glucose metabolism, e.g. obesity, type-2 diabetes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2800/00—Nucleic acids vectors
- C12N2800/30—Vector systems comprising sequences for excision in presence of a recombinase, e.g. loxP or FRT
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2830/00—Vector systems having a special element relevant for transcription
- C12N2830/001—Vector systems having a special element relevant for transcription controllable enhancer/promoter combination
- C12N2830/002—Vector systems having a special element relevant for transcription controllable enhancer/promoter combination inducible enhancer/promoter combination, e.g. hypoxia, iron, transcription factor
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2830/00—Vector systems having a special element relevant for transcription
- C12N2830/008—Vector systems having a special element relevant for transcription cell type or tissue specific enhancer/promoter combination
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2830/00—Vector systems having a special element relevant for transcription
- C12N2830/80—Vector systems having a special element relevant for transcription from vertebrates
- C12N2830/85—Vector systems having a special element relevant for transcription from vertebrates mammalian
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
- G01N2333/475—Assays involving growth factors
- G01N2333/495—Transforming growth factor [TGF]
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2500/00—Screening for compounds of potential therapeutic value
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Zoology (AREA)
- Animal Behavior & Ethology (AREA)
- Genetics & Genomics (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Environmental Sciences (AREA)
- Molecular Biology (AREA)
- Biotechnology (AREA)
- Biomedical Technology (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Biochemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biophysics (AREA)
- Animal Husbandry (AREA)
- Biodiversity & Conservation Biology (AREA)
- Wood Science & Technology (AREA)
- General Engineering & Computer Science (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Immunology (AREA)
- Hematology (AREA)
- Gastroenterology & Hepatology (AREA)
- Physics & Mathematics (AREA)
- Microbiology (AREA)
- Toxicology (AREA)
- Cell Biology (AREA)
- Diabetes (AREA)
- Neurology (AREA)
- Plant Pathology (AREA)
- Urology & Nephrology (AREA)
- Endocrinology (AREA)
Abstract
【解決手段】GDF-8(ミオスタチン)受容体を含む実質的に精製された増殖分化因子(GDF)受容体と共にその機能的ペプチド部分、GDF受容体またはその機能的ペプチド部分の仮想表示、また、細胞におけるミオスタチンシグナル伝達に影響を及ぼす物質を細胞に接触させることによって、細胞に及ぼすミオスタチンの影響を調節する方法、さらに、被験者の筋細胞または脂肪組織細胞におけるミオスタチンシグナル伝達を調節することによって、被験者における筋または脂肪組織の異常な量、発達、または代謝活性を少なくとも部分的に特徴とする病態の重症度を改善する方法、ミオスタチンシグナル伝達に影響を及ぼす物質を生物に投与することによって、真核生物における筋組織または脂肪組織の増殖を調節する方法など。
【選択図】なし
Description
本発明は、一般的に増殖分化因子(GDF)受容体に関し、より詳しくはGDF-8(ミオスタチン)受容体、細胞においてミオスタチンシグナル伝達に影響を及ぼす組成物、および細胞におけるミオスタチンシグナル伝達を調節するためにそのような組成物を用いる方法に関する。
アメリカにおいて、体重を減らそうと考えている人が消費する時間、労力、およびお金の量は驚異的である。これらの人の多くにとって、目標は単に外見を良くすることではなく、より重要なことは、過体重であることに関連した避けて通れない医学的問題を回避することである。
本発明は、プロミオスタチンポリペプチドの実質的に精製されたペプチド部分を提供する。これまで増殖分化因子-8(GDF-8)と呼ばれていたプロミオスタチンは、アミノ末端プロドメインとC末端成熟ミオスタチンペプチド(米国特許第5,827,733号を参照のこと)とを含む。ミオスタチン活性は、プロミオスタチンからの切断後の成熟ミオスタチンペプチドによって示される。このように、プロミオスタチンは、蛋白質分解によって切断されて活性ミオスタチンを生じる前駆体ポリペプチドである。本明細書に開示するように、ミオスタチンプロドメインは、ミオスタチン活性、GDF-11活性またはその双方を阻害することができる。
(1)BLASTPおよびBLAST3は、蛋白質配列データベースに対してアミノ酸問い合わせ配列を比較する;
(2)BLASTNは、ヌクレオチド配列データベースに対してヌクレオチド問い合わせ配列を比較する;
(3)BLASTXは、蛋白質配列データベースに対する問い合わせヌクレオチド配列(双方の鎖)の6個のフレーム概念的翻訳産物を比較する;
(4)TBLASTNは、全ての6個のリーディングフレーム(双方の鎖)において翻訳されたヌクレオチド配列データベースに対して問い合わせ蛋白質配列を比較する;および
(5)TBLASTXは、ヌクレオチド配列データベースの6個のフレーム翻訳に対するヌクレオチド問い合わせ配列の6個のフレーム翻訳を比較する。
ミオスタチンは用量依存的に作用する
本実施例は、筋増殖の阻害におけるミオスタチンの活性がインビボでミオスタチン発現レベルに依存することを示す。
ミオスタチンの作用はノックアウトマウスの年齢と共に減少する
本実施例は、野生型マウスとホモ接合ミオスタチンノックアウトマウスのあいだの体重の差の減少が、変異体マウスの筋重量の減少に関連していることを証明する。
ミオスタチンは用量依存的に脂肪の蓄積に影響を及ぼす
本実施例は、ミオスタチンノックアウトマウスが脂肪を蓄積させることができないこと、および脂肪蓄積の減少がインビボでのミオスタチン発現レベルに関連していることを証明する。
代謝に及ぼすミオスタチンの影響
本実施例は、血清インスリンとグルコースレベルが代謝活性と共にミオスタチン発現レベルによって影響を受けることを証明する。
ミオスタチンは遺伝的肥満マウスにおける脂肪蓄積に影響を及ぼす
本実施例は、ミオスタチン発現の欠如が、肥満の遺伝子モデルであるマウスにおいて脂肪の蓄積を抑制することを証明する。
組換えミオスタチンの精製
本実施例は、組換えミオスタチンを調製および単離する方法を提供する。
ミオスタチンはアクチビン受容体と特異的に相互作用する
本実施例は、ミオスタチンが培養細胞上で発現されたアクチビンII型受容体に特異的に結合すること、およびこの特異的結合がミオスタチンプロドメインによって阻害されることを証明する。
ミオスタチンレベルの増加は体重減少を誘導する
本実施例は、ミオスタチンレベルの上昇がインビボでの実質的な体重減少につながりうることを証明する。
アクチビン受容体に対するミオスタチン結合の特徴付け
本実施例は、アクチビン受容体に対するミオスタチンの結合と、インビボでミオスタチンによって生じた生物作用との関係の特徴を調べる方法を記述する。
肥満およびII型糖尿病の遺伝子モデルにおけるミオスタチンの作用の特徴付け
本実施例は、肥満またはII型糖尿病の治療におけるミオスタチンの作用を決定する方法を記述する。
ミオスタチン活性に影響を及ぼしうるドミナントネガティブポリペプチドを発現するトランスジェニックマウスの特徴付け
本実施例は、ミオスタチン発現またはミオスタチンシグナル伝達を阻害しうるドミナントネガティブポリペプチドを発現することによって生後にミオスタチンの作用の特徴を調べる方法を記述する。
生後にミオスタチン活性を調節することを用いて、筋繊維数(過形成)および筋繊維の大きさ(肥大)に及ぼすミオスタチンの作用を調べることができる。ミオスタチン遺伝子が動物の一生の間で一定期間欠失している条件付ミオスタチンノックアウトマウスをこれらの試験に用いることができる。creレコンビナーゼと組み合わせたtet調節物質は、そのようなマウスを作製するためのシステムを提供する。この系において、creの発現は、ドキシサイクリンの投与によって誘導される。
ミオスタチン導入遺伝子を含むトランスジェニックマウスも同様に調べて、ミオスタチンの発現時に生じた作用を、ミオスタチン発現CHO細胞を含むヌードマウスにおいて認められた作用と比較することができる。上記と同様に、ミオスタチンは、条件(tet)および組織特異的調節エレメントの制御下に置くことができ、ヌードマウスにおいて認められたものと類似の消耗性症候群が起こるか否かを決定するために、トランスジェニックマウスにおけるミオスタチンの発現を調べることができる。ミオスタチン導入遺伝子は、例えば、導入遺伝子が内因性のミオスタチン遺伝子と区別できるように、SV40に由来するプロセシングシグナルを含みうる。
骨格筋において特異的に発現されるTGF-βシグナル伝達経路の成分を含みうる、ミオスタチンシグナル伝達経路のいずれかのドミナントネガティブ型を含むトランスジェニックマウスを作製することができる。本明細書において開示するように、アクチビンII型受容体によって誘導される経路を通してシグナル伝達を媒介するSmad蛋白質は、ミオスタチンシグナル伝達に関係しうる。
カヘキシアの誘導に及ぼすミオスタチン作用の特徴付け
本実施例は、カヘキシアの発症および進行におけるミオスタチンシグナル伝達の役割を調べる方法について記述する。
増殖分化因子-8(GDF-8)およびGDF-11受容体の同定と特徴付け
本実施例は、GDF-8(ミオスタチン)とGDF-11の細胞表面受容体を同定して特徴を調べる方法を記述する。
GDF-11ノックアウトマウスの作製と特徴付け
いくつかの局面におけるGDF-11ノックアウトマウスの表現型は、アクチビンIIB型受容体(Act RIIB)を含むTGF-βスーパーファミリーのいくつかのメンバーの受容体の欠失を有するマウスの表現型に類似する。GDF-11の生物機能を決定するために、GDF-11遺伝子を胚性幹細胞において相同的ターゲティングによって破壊した。
ミオスタチンプロペプチド、フォリスタチンまたはドミナントネガティブACT RIIBを発現するトランスジェニックマウスの作製
ミオスタチンの精製
ミオスタチン発現構築物の増幅コピーを有するチャイニーズハムスター卵巣(CHO)細胞株に、前駆体蛋白質のプロセシングを改善するために、フリンプロテアーゼPACEの発現構築物(Monique Davies氏の好意による提供)をトランスフェクトした。条件培地(セルトレンズ社の調製、ミドルタウン、メリーランド州)を、ヒドロキシアパタイト(200 mM燐酸ナトリウム、pH 7.2によって溶出)、レンチルレクチンセファロース(50 mMトリス、pH 7.4、500 mM NaCl、500 mMメチルマンノースによって溶出)、DEAEアガロース(50 mMトリス、pH 7.4、50 mM NaCl中でカラムの中を通過した材料を集める)、およびヘパリンセファロース(50 mMトリス、pH 7.4、200 mM NaClによって溶出)に連続的に通過させた。ヘパリンカラムからの溶出液を逆相C4 HPLCカラムに結合させて、0.1%トリフルオロ酢酸中でアセトニトリル勾配によって溶出した。成熟C-末端蛋白質に対する抗体は既に記述されている(参照として本明細書に組み入れられる、米国特許第5,827,733号を参照のこと)。プロペプチドに対する抗体を作製するために、アミノ酸122〜261位に及ぶヒトミオスタチン蛋白質の一部をRSETベクター(インビトロジェン社、サンジエゴ、カリフォルニア州)を用いて細菌に発現させ、ニッケルキレートクロマトグラフィーによって精製して、ウサギに注射した。免疫は、スプリングバレー研究所(ウッドバイン、メリーランド州)が行った。
クロラミンT法(Frolik, C.A., Wakefield, L.M., Smith, D.M., and Sporn, M.B.(1984)、J. Biol. Chem. 259、10995〜11000)を用いて、精製ミオスタチンに放射性ヨウ素を標識した。6または12ウェルプレートにおいて増殖させたCOS-7細胞に、リポフェクタミン(ギブコ社、ロックビル、メリーランド州)を用いて、pCMV5またはpCMV5/受容体構築物1〜2μgをトランスフェクトした。クロスリンク実験は、記述のようにトランスフェクションの2日後に行った(Franzen, P.、ten Dijke, P.、Ichijo, H.、Yamashita, H.、Schultz, P.、Heldin、C.H.、およびMiyazono, K.(1993)、Cell 75:681〜692)。定量的受容体結合アッセイ法を行うために、細胞単層を、1 mg/ml BSAを含むPBSによって2回洗浄して、様々な濃度の非標識ミオスタチン、プロペプチド、またはフォリスタチンの存在下または非存在下で、4℃で標識ミオスタチンと共にインキュベートした。次に、細胞を同じ緩衝液によって3回洗浄して、0.5 N NaOH中で溶解し、γカウンターにおいて計数した、特異的結合は、Act RIIBをトランスフェクトした細胞と、ベクターをトランスフェクトした細胞との結合ミオスタチンの差として計算した。特異的結合を計算するこの方法は、プロペプチドを加えても同様に非特異的結合が濃度依存的に減少することから、プロペプチドの影響を評価するために特に重要であった。
アミノ酸1〜174位に及ぶマウスAct RIIBの切断型、アミノ酸1〜267位に及ぶマウスミオスタチンプロペプチド、およびヒトフォリスタチン短縮型をコードするDNAを、ミオシン軽鎖プロモーターおよび1/3エンハンサー(McPherron, A.C.とLee, S.J.、(1993)、J. Biol. Chem. 268:3444〜3449)を含むMDAF2ベクターにクローニングした。ミオシン軽鎖調節配列とSV40プロセシング部位とを含む精製導入遺伝子をマイクロインジェクションのために用いた。マイクロインジェクションおよび胚の移入は全て、ジョンホプキンス大学メディカルスクールのトランスジェニックコア施設(John Hopkins of Medicine Trandgenic Core Facility)が行った。ハイブリッドSJL/C57BL/6バックグラウンドのトランスジェニック創始動物を野生型C57BL/6マウスと交配させて、研究は全てF1子孫を用いて行った。筋重量の分析に関して、個々の筋肉をほぼ全ての動物の両側から切除して、左右の筋重量の平均値を用いた。線維数と大きさの分析は記述通りに行った(McPherron, A.C.、Lawler, A.M.、およびLee, S.J.(1997)、Nature 387:83〜90)。RNA単離およびノザン分析は記述通りに行った(McPherron, A.C.、およびLee, S.J(1993)、J. Biol.Chem. 268:3444〜3449)。
Claims (42)
- 核酸配列が、対応する非トランスジェニック動物と比較して切断型アクチビンII型受容体レベルの上昇と、動物における筋重量の増加とが起こるように発現される、そのゲノムが、機能的に結合して動物のゲノムに組み入れられる、切断型アクチビンII型受容体遺伝子と筋特異的プロモーターとを含む核酸配列を含む、ヒト以外のトランスジェニック動物。
- 筋特異的プロモーターがミオシン軽鎖プロモーター/エンハンサーである、請求項1記載のトランスジェニック動物。
- アクチビンII型受容体がRIIAまたはRIIBである、請求項1記載のトランスジェニック動物。
- 切断型アクチビンRIIB受容体がキナーゼ活性を欠損する、請求項3記載のトランスジェニック動物。
- 切断型アクチビンRIIB受容体がアクチビンRIIBのアミノ酸残基1〜174位を含む、請求項1記載のトランスジェニック動物。
- 核酸配列が、対応する非トランスジェニック動物と比較して、動物におけるミオスタチンプロドメインレベルの上昇と筋重量の増加とが起こるように発現される、そのゲノムが、機能的に結合して動物のゲノムに組み入れられる、ミオスタチンプロドメインと筋特異的プロモーターとを含む核酸配列を含む、ヒト以外のトランスジェニック動物。
- ミオスタチンプロドメインが、配列番号:2、4、6、8、10、12、14、16、18、および20、またはミオスタチンプロドメインの機能的ペプチド部分からなる群より選択されるプロミオスタチンポリペプチドのアミノ酸残基約1〜262位を含む、請求項6記載のトランスジェニック動物。
- ミオスタチンプロドメインが、以下からなる群より選択されるアミノ酸配列を含む、請求項6記載のトランスジェニック動物:
配列番号:4に記載のアミノ酸残基約20〜263位;
配列番号:2に記載のアミノ酸残基約20〜262位;
配列番号:10に記載のアミノ酸残基約20〜262位;
配列番号:12に記載のアミノ酸残基約20〜262位;
配列番号:8に記載のアミノ酸残基約20〜262位;
配列番号:6に記載のアミノ酸残基約20〜263位;
配列番号:18に記載のアミノ酸残基約20〜262位;
配列番号:14に記載のアミノ酸残基約20〜262位;
配列番号:16に記載のアミノ酸残基約20〜262位;
配列番号:20に記載のアミノ酸残基約20〜262位;および
その機能的ペプチド部分。 - ミオスタチンプロドメインがミオスタチンシグナルペプチドをさらに含む、請求項6記載のトランスジェニック動物。
- 筋特異的プロモーターがミオシン軽鎖プロモーター/エンハンサーである、請求項6記載のトランスジェニック動物。
- 核酸配列が、対応する非トランスジェニック動物と比較して、動物におけるフォリスタチンレベルの上昇と筋重量の増加とが起こるように発現される、そのゲノムが、機能的に結合して動物のゲノムに組み入れられる、フォリスタチン遺伝子と筋特異的プロモーターとを含む核酸配列を含む、ヒト以外のトランスジェニック動物。
- 筋特異的プロモーターがミオシン軽鎖プロモーター/エンハンサーである、請求項11記載のトランスジェニック動物。
- 筋特異的制御配列に機能的に結合した切断型アクチビンRIIB受容体遺伝子をコードするDNAセグメントを含む発現カセット。
- 筋特異的プロモーターがミオシン軽鎖プロモーター/エンハンサーである、請求項13記載の発現カセット。
- 筋特異的制御配列に機能的に結合したミオスタチンプロドメイン遺伝子をコードするDNAセグメントを含む発現カセット。
- 筋特異的プロモーターがミオシン軽鎖プロモーター/エンハンサーである、請求項15記載の発現カセット。
- 筋特異的制御配列に機能的に結合したフォリスタチン遺伝子をコードするDNAセグメントを含む発現カセット。
- 筋特異的プロモーターが、ミオシン軽鎖プロモーター/エンハンサーである、請求項17記載の発現カセット。
- 発現カセットが動物のゲノムに組み入れられ、カセットが、動物におけるフォリスタチンレベルが上昇して、その結果、対応する非トランスジェニック動物と比較してトランスジェニック動物における筋重量の増加が起こるように発現される、トランスジェニック動物の細胞において、請求項17記載の発現カセットを発現させることを含む、トランスジェニック動物においてフォリスタチンを組織特異的に発現させる方法。
- 細胞が、切断型アクチビンII型受容体、ミオスタチンプロドメイン、またはフォリスタチンをそれぞれ発現する、請求項1、6、または11のいずれか一項に記載の動物から単離した細胞または細胞株。
- ミオスタチンをフォリスタチンに接触させて、それによって受容体との結合を阻害することを含む、アクチビンII型受容体に対するミオスタチン結合を阻害する方法。
- 結合の阻害がミオスタチンのC-末端を通して行われる、請求項21記載の方法。
- アクチビン受容体がAct RIIAまたはAct RIIBである、請求項21記載の方法。
- 筋細胞におけるDNA構築物の発現によって動物の筋重量の増加が起こる、そのゲノムが、筋細胞における発現にとって有効な内因性フォリスタチン遺伝子に対して異種のプロモーターに機能的に結合したフォリスタチン蛋白質をコードするDNAセグメントを含むDNA構築物を含む、ヒト以外のトランスジェニック動物。
- DNA構築物が動物の祖先に導入されている、請求項24記載のヒト以外の動物。
- DNA構築物が胚の段階で動物または該動物の祖先に導入される、請求項24記載のヒト以外の動物。
- フォリスタチン蛋白質が、野生型と比較してフォリスタチン蛋白質の切断型、変異型、または他の変種型である、請求項24記載のヒト以外の動物。
- DNA構築物が、フォリスタチン蛋白質をコードするDNAセグメントを含むMDAF2発現プラスミドに存在する、請求項24記載のヒト以外の動物。
- 動物が哺乳類である、請求項24記載のヒト以外の動物。
- 哺乳類がマウスである、請求項29記載のヒト以外の動物。
- 哺乳類がブタである、請求項29記載のヒト以外の動物。
- 哺乳類がウシである、請求項29記載のヒト以外の動物。
- 動物がトリ種である、請求項24記載のヒト以外の動物。
- トリ種がニワトリまたは七面鳥である、請求項33記載のヒト以外の動物。
- 動物が水生種である、請求項24記載のヒト以外の動物。
- 水生種が魚である、請求項35記載のヒト以外の動物。
- 魚が、サケ、マス、チャー、アユ、コイ、ヨーロッパフナ、キンギョ、ウグイ、シラス、ウナギ、アナゴ、コイワシ、ゼブラフィッシュ、トビウオ、ハタ科の魚、タイ科の魚、パロットバス、フエダイ、サバ、クロマグロ、マグロ、ハガツオ、黄色の尾をもつ魚、岩間の魚、フルーク、ソール、ヒラメ、フグ、またはモンガラカワハギである、請求項36記載のヒト以外の動物。
- 水生種が、ハマグリ、コックル、イガイ、タマキビガイ、ホタテ貝、ホラガイ、マキガイ、ナマコ、アークシェル、カキ、リュウテンサザエ科の貝、アワビ、ロブスター、クルマエビ、エビ、カニ、シャコ、クリール、ランゴスチノ、イセエビ/ザリガニ、環形動物、ワニ、カメ、カエル、またはウニである、請求項35記載のヒト以外の動物。
- 動物がヒツジである、請求項24記載のヒト以外の動物。
- 以下を含む、ヒト以外のキメラ動物を作製する方法:
動物の卵巣から卵子を得る段階;
インビトロで卵子を成熟させる段階;
インビトロで成熟した卵子を受精させて受精卵を形成する段階;
切断型アクチビンII型受容体、ミオスタチンプロペプチド、またはフォリスタチンをコードするDNA配列と、ポリペプチドをコードするDNA配列の発現を促進する制御配列とを機能的に結合させて含む核酸構築物を、インビトロで受精卵に導入する段階;
受精卵を着床前段階の胚までインビトロで成熟させる段階;および
雌性動物が胚を妊娠してキメラ動物を産む、レシピエント雌性動物に胚を移植する段階。 - 以下を含む、筋重量が増加した動物の食糧を作製する方法:
a)動物の前核胚の生殖細胞に、フォリスタチン、ミオスタチンプロペプチド、または切断型アクチビンII型受容体をコードする導入遺伝子を導入する段階;
b)偽妊娠雌性動物の卵管に胚を着床させて、それによって胚を妊娠満期まで成熟させる段階;
c)導入遺伝子陽性子孫を同定するために導入遺伝子の有無に関して子孫を試験する段階;
d)さらなる導入遺伝子陽性子孫を同定するために、導入遺伝子陽性子孫を交配させる段階;および
e)子孫を加工して食糧を得る段階。 - 以下を含む、筋重量が増加したトリ、ブタ、魚、またはウシの食品を作製する方法:
a)フォリスタチン、ミオスタチンプロペプチド、または切断型アクチビンII型受容体をコードする導入遺伝子を、トリ、ブタ、魚、またはウシ動物の胚に導入する段階;
b)子孫が孵化する条件で胚を培養する段階;
c)導入遺伝子陽性子孫を同定するために導入遺伝子の有無に関して子孫を試験する段階;
d)導入遺伝子陽性子孫を交配する段階;および
e)子孫を加工して食糧を得る段階。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US09/841,730 US6891082B2 (en) | 1997-08-01 | 2001-04-24 | Transgenic non-human animals expressing a truncated activintype II receptor |
US09/841,730 | 2001-04-24 |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2008116224A Division JP4361955B2 (ja) | 2001-04-24 | 2008-04-25 | 筋重量を増加させるためのフォリスタチンの使用方法 |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2009261402A true JP2009261402A (ja) | 2009-11-12 |
JP5425537B2 JP5425537B2 (ja) | 2014-02-26 |
Family
ID=25285564
Family Applications (4)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2002582882A Pending JP2004537982A (ja) | 2001-04-24 | 2002-04-24 | 筋重量を増加させるためのフォリスタチンの使用方法 |
JP2008116224A Expired - Fee Related JP4361955B2 (ja) | 2001-04-24 | 2008-04-25 | 筋重量を増加させるためのフォリスタチンの使用方法 |
JP2008298119A Expired - Fee Related JP5004930B2 (ja) | 2001-04-24 | 2008-11-21 | 筋重量を増加させるためのフォリスタチンの使用方法 |
JP2009147316A Expired - Fee Related JP5425537B2 (ja) | 2001-04-24 | 2009-06-22 | 筋重量を増加させるためのフォリスタチンの使用方法 |
Family Applications Before (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2002582882A Pending JP2004537982A (ja) | 2001-04-24 | 2002-04-24 | 筋重量を増加させるためのフォリスタチンの使用方法 |
JP2008116224A Expired - Fee Related JP4361955B2 (ja) | 2001-04-24 | 2008-04-25 | 筋重量を増加させるためのフォリスタチンの使用方法 |
JP2008298119A Expired - Fee Related JP5004930B2 (ja) | 2001-04-24 | 2008-11-21 | 筋重量を増加させるためのフォリスタチンの使用方法 |
Country Status (15)
Country | Link |
---|---|
US (6) | US6891082B2 (ja) |
EP (2) | EP1395113A4 (ja) |
JP (4) | JP2004537982A (ja) |
KR (3) | KR20090032148A (ja) |
CN (1) | CN1520256B (ja) |
AU (1) | AU2002307564B2 (ja) |
BR (1) | BR0209191A (ja) |
CA (2) | CA2807478A1 (ja) |
HU (1) | HUP0401542A2 (ja) |
IL (2) | IL158420A0 (ja) |
NO (1) | NO20034693L (ja) |
NZ (1) | NZ528963A (ja) |
PL (1) | PL367201A1 (ja) |
WO (1) | WO2002085306A2 (ja) |
ZA (1) | ZA200308021B (ja) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2323133A2 (en) | 2009-11-16 | 2011-05-18 | Sony Corporation | Disc cartridge |
JP2012067081A (ja) * | 2010-08-24 | 2012-04-05 | Okayama Univ | 疼痛の治療剤 |
Families Citing this family (91)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7393682B1 (en) * | 1993-03-19 | 2008-07-01 | The Johns Hopkins University School Of Medicine | Polynucleotides encoding promyostatin polypeptides |
US7566768B1 (en) | 1995-10-26 | 2009-07-28 | The Johns Hopkins University School Of Medicine | Promyostatin peptides and methods of using same |
US6656475B1 (en) * | 1997-08-01 | 2003-12-02 | The Johns Hopkins University School Of Medicine | Growth differentiation factor receptors, agonists and antagonists thereof, and methods of using same |
US6891082B2 (en) | 1997-08-01 | 2005-05-10 | The Johns Hopkins University School Of Medicine | Transgenic non-human animals expressing a truncated activintype II receptor |
TWI329129B (en) | 2001-02-08 | 2010-08-21 | Wyeth Corp | Modified and stabilized gdf propeptides and uses thereof |
WO2003022040A2 (en) * | 2001-09-13 | 2003-03-20 | California Institute Of Technology | Method for producing transgenic animals |
US7320789B2 (en) * | 2001-09-26 | 2008-01-22 | Wyeth | Antibody inhibitors of GDF-8 and uses thereof |
BR0307871A (pt) * | 2002-02-21 | 2005-04-12 | Wyeth Corp | Proteìnas contendo domìnio de folistatina |
US7572599B2 (en) * | 2002-09-16 | 2009-08-11 | The Johns Hopkins University School Of Medicine | Metalloprotease activation of myostatin, and methods of modulating myostatin activity |
AR047392A1 (es) | 2002-10-22 | 2006-01-18 | Wyeth Corp | Neutralizacion de anticuerpos contra gdf 8 y su uso para tales fines |
US20040223966A1 (en) * | 2002-10-25 | 2004-11-11 | Wolfman Neil M. | ActRIIB fusion polypeptides and uses therefor |
MEP57508A (en) * | 2002-12-20 | 2011-05-10 | Amgen Inc | Binding agents which inhibit myostatin |
MXPA05012965A (es) * | 2003-06-02 | 2006-03-09 | Wyeth Corp | Uso de inhibidores de miostatina (gdf8) en conjuncion con corticoesteroides para el tratamiento de desordenes neuromusculares y composiciones farmaceuticas para ello. |
WO2005025601A1 (en) * | 2003-09-15 | 2005-03-24 | Monash University | Follistatin isoforms and uses thereof |
US7246056B1 (en) * | 2003-09-26 | 2007-07-17 | The Mathworks, Inc. | Runtime parameter mapping for system simulation |
US7456149B2 (en) | 2004-03-02 | 2008-11-25 | Acceleron Pharma, Inc. | ALK7 and myostatin inhibitors and uses thereof |
JP4688483B2 (ja) * | 2004-04-15 | 2011-05-25 | 株式会社テクノネットワーク四国 | フォリスタチン変異体ポリペプチド |
ES2426005T3 (es) | 2004-07-23 | 2013-10-18 | Acceleron Pharma Inc. | Polipéptidos del receptor ACTRII, procedimientos y composiciones |
WO2006102574A2 (en) * | 2005-03-23 | 2006-09-28 | Wyeth | Detection of gdf-8 modulating agents |
JP5415071B2 (ja) * | 2005-08-19 | 2014-02-12 | ワイス・エルエルシー | Gdf−8に対するアンタゴニスト抗体ならびにalsおよびその他のgdf−8関連障害の処置における使用 |
CN100380118C (zh) * | 2005-09-07 | 2008-04-09 | 集美大学 | 鲍鱼种类鉴别方法 |
US8067562B2 (en) * | 2005-11-01 | 2011-11-29 | Amgen Inc. | Isolated nucleic acid molecule comprising the amino acid sequence of SEQ ID NO:1 |
US8128933B2 (en) | 2005-11-23 | 2012-03-06 | Acceleron Pharma, Inc. | Method of promoting bone growth by an anti-activin B antibody |
AU2006318449B2 (en) | 2005-11-23 | 2012-07-05 | Acceleron Pharma Inc. | Activin-actRIIa antagonists and uses for promoting bone growth |
CA2856436A1 (en) * | 2005-12-06 | 2007-06-14 | Amgen Inc. | Uses of myostatin antagonists |
CN100347298C (zh) * | 2005-12-30 | 2007-11-07 | 中国水产科学研究院黄海水产研究所 | 鱼类肌肉生长抑素mstn基因克隆及其基因打靶载体构建 |
US20090142336A1 (en) * | 2006-02-28 | 2009-06-04 | Trustees Of Boston University | Metabolic regulators and uses thereof |
US20070275036A1 (en) * | 2006-05-18 | 2007-11-29 | Celldyne Biopharma, Llc | Avian follistatin product |
US7663019B2 (en) * | 2006-05-24 | 2010-02-16 | North Carolina State University | Transgenic snakes and methods of making |
CN104524548A (zh) * | 2006-12-18 | 2015-04-22 | 阿塞勒隆制药公司 | 活化素-actrii拮抗剂及在提高红细胞水平中的用途 |
US20100028332A1 (en) * | 2006-12-18 | 2010-02-04 | Acceleron Pharma Inc. | Antagonists of actriib and uses for increasing red blood cell levels |
US8895016B2 (en) | 2006-12-18 | 2014-11-25 | Acceleron Pharma, Inc. | Antagonists of activin-actriia and uses for increasing red blood cell levels |
CA2677007A1 (en) * | 2007-02-01 | 2008-08-07 | Acceleron Pharma Inc. | Activin-actriia antagonists and uses for treating or preventing breast cancer |
TWI782836B (zh) | 2007-02-02 | 2022-11-01 | 美商艾瑟勒朗法瑪公司 | 衍生自ActRIIB的變體與其用途 |
TWI667038B (zh) * | 2007-02-09 | 2019-08-01 | 美商艾瑟勒朗法瑪公司 | 包含ActRIIa-Fc融合蛋白的醫藥組合物;ActRIIa-Fc融合蛋白於治療或預防與癌症相關的骨質流失之用途;ActRIIa-Fc融合蛋白於治療或預防多發性骨髓瘤之用途 |
US8501678B2 (en) | 2007-03-06 | 2013-08-06 | Atara Biotherapeutics, Inc. | Variant activin receptor polypeptides and uses thereof |
TWI573802B (zh) * | 2007-03-06 | 2017-03-11 | 安美基公司 | 變異之活動素受體多肽及其用途 |
WO2008109779A2 (en) * | 2007-03-07 | 2008-09-12 | The Johns Hopkins University | Use of follistatin-like related gene (flrg) to increase muscle mass |
SI2170396T1 (sl) | 2007-08-03 | 2017-04-26 | Summit (Oxford) Limited | Kombinacije zdravil za zdravljenje duchennove mišične distrofije |
GB0715087D0 (en) | 2007-08-03 | 2007-09-12 | Summit Corp Plc | Drug combinations for the treatment of duchenne muscular dystrophy |
US7960343B2 (en) * | 2007-09-18 | 2011-06-14 | Acceleron Pharma Inc. | Activin-ActRIIa antagonists and uses for decreasing or inhibiting FSH secretion |
WO2009111793A2 (en) * | 2008-03-07 | 2009-09-11 | Myoscience, Inc. | Subdermal tissue remodeling using myostatin, methods and related systems |
KR20220002710A (ko) | 2008-06-26 | 2022-01-06 | 악셀레론 파마 인코포레이티드 | 액티빈-actriia 길항물질을 투약하는 방법 및 치료된 환자의 모니터링 |
US8216997B2 (en) | 2008-08-14 | 2012-07-10 | Acceleron Pharma, Inc. | Methods for increasing red blood cell levels and treating anemia using a combination of GDF traps and erythropoietin receptor activators |
SI3750552T1 (sl) | 2008-08-14 | 2023-10-30 | Acceleron Pharma Inc. | GDF pasti |
MA32936B1 (fr) | 2008-11-26 | 2012-01-02 | Amgen Inc | Polypeptides de recepteur stabilises et leurs utilisations |
CA2749544A1 (en) * | 2009-01-13 | 2010-07-22 | Acceleron Pharma Inc. | Methods for increasing adiponectin |
EA027071B1 (ru) * | 2009-04-27 | 2017-06-30 | Новартис Аг | АНТИТЕЛО К ActRIIB И СОДЕРЖАЩАЯ ЕГО КОМПОЗИЦИЯ |
WO2010134686A2 (ko) * | 2009-05-20 | 2010-11-25 | 강릉원주대학교산학협력단 | 마이오스타틴 억제 활성을 갖는 가용성 마이오스타틴 프로도메인 재조합 단백질 및 그의 용도 |
EP3845239A1 (en) * | 2009-06-08 | 2021-07-07 | Acceleron Pharma Inc. | Use of anti-actriib proteins for increasing thermogenic adipocytes |
CN107267520A (zh) | 2009-06-12 | 2017-10-20 | 阿塞勒隆制药公司 | 截短的actriib‑fc融合蛋白 |
BR112012005225B8 (pt) * | 2009-09-09 | 2023-01-10 | Acceleron Pharma Inc | Uso de uma proteína de fusão actriib-fc para o tratamento de um transtorno relacionado ao osso ou associado à perda de músculo por crescimento muscular insuficiente |
ES2869864T3 (es) * | 2009-11-03 | 2021-10-26 | Acceleron Pharma Inc | Procedimientos para el tratamiento de la enfermedad del hígado graso |
US8710016B2 (en) | 2009-11-17 | 2014-04-29 | Acceleron Pharma, Inc. | ActRIIB proteins and variants and uses therefore relating to utrophin induction for muscular dystrophy therapy |
WO2011102483A1 (ja) * | 2010-02-19 | 2011-08-25 | 独立行政法人理化学研究所 | ヒトTGF-βのLAPに結合する抗体 |
CN105457016B (zh) | 2010-09-22 | 2022-06-24 | 科罗拉多大学董事会 | Smad7的治疗应用 |
CN103298832A (zh) | 2010-11-08 | 2013-09-11 | 阿塞勒隆制药公司 | Actriia结合剂及其用途 |
CN102648977B (zh) * | 2011-02-25 | 2014-12-10 | 中国科学院上海生命科学研究院 | 滤泡素抑制素样蛋白1在调节钠钾atp酶活性中的用途 |
CA2859504A1 (en) | 2011-12-19 | 2013-07-18 | Amgen Inc. | Variant activin receptor polypeptides, alone or in combination with chemotherapy, and uses thereof |
CN104428009A (zh) * | 2012-02-07 | 2015-03-18 | 全球生物疗法美国有限公司 | 核酸输送的区室化方法及其组合物和应用 |
EP2875359A4 (en) | 2012-03-30 | 2015-08-19 | Charles R Drew University Of Medicine And Science | COMPOSITIONS AND METHODS FOR TREATING OR PREVENTING METABOLISM SYNDROME DISEASES |
MY177331A (en) | 2012-06-15 | 2020-09-12 | Pfizer | Improved antagonist antibodies against gdf-8 and uses therefor |
RS60318B1 (sr) | 2012-08-01 | 2020-07-31 | Ikaika Therapeutics Llc | Ublažavanje tkivnog oštećenja i fibroze pomoću anti-ltbp4 antitela |
IL267663B (en) * | 2012-10-24 | 2022-09-01 | Celgene Corp | A biomarker for use in the treatment of anemia |
CA2890217C (en) | 2012-11-02 | 2021-07-20 | Yifu FANG | Activin-actrii antagonists and uses for treating bone and other disorders |
SG11201505960VA (en) | 2013-02-01 | 2015-08-28 | Santa Maria Biotherapeutics Inc | Administration of an anti-activin-a compound to a subject |
SG11201507045TA (en) | 2013-03-08 | 2015-10-29 | Univ Colorado Regents | Ptd-smad7 therapeutics |
CA2911514A1 (en) * | 2013-05-06 | 2014-11-13 | Scholar Rock, Inc. | Compositions and methods for growth factor modulation |
US10010498B2 (en) | 2014-06-04 | 2018-07-03 | Acceleron Pharma Inc. | Methods for treatment of amyotrophic lateral sclerosis with follistatin fusion proteins |
WO2015187977A1 (en) | 2014-06-04 | 2015-12-10 | Acceleron Pharma, Inc. | Methods and compositions for treatment of disorders with follistatin polypeptides |
WO2015192111A1 (en) | 2014-06-13 | 2015-12-17 | Acceleron Pharma, Inc. | Methods and compositions for treating ulcers |
MA41052A (fr) | 2014-10-09 | 2017-08-15 | Celgene Corp | Traitement d'une maladie cardiovasculaire à l'aide de pièges de ligands d'actrii |
JP6706617B2 (ja) | 2014-11-06 | 2020-06-10 | スカラー ロック インコーポレイテッドScholar Rock,Inc. | 抗プロ/潜在型−ミオスタチン抗体およびその使用 |
BR112017011722A2 (pt) | 2014-12-03 | 2018-02-27 | Acceleron Pharma Inc | antagonistas de activina-actrii e usos para o tratamento de anemia |
SG10201906471PA (en) | 2015-01-14 | 2019-09-27 | Brigham & Womens Hospital Inc | Treatment of cancer with anti-lap monoclonal antibodies |
CA2980757A1 (en) | 2015-03-26 | 2016-09-29 | Acceleron Pharma Inc. | Follistatin-related fusion proteins and uses thereof |
PL3286206T3 (pl) | 2015-04-22 | 2021-09-13 | Biogen Ma Inc. | Nowe hybrydowe białka pułapki na ligand actriib do leczenia chorób powodujących zanik mięśni |
MX2018003196A (es) | 2015-09-15 | 2019-05-16 | Scholar Rock Inc | Anticuerpos anti-promiostatina o miostatina latente y usos de los mismos. |
CN105372276B (zh) * | 2015-11-24 | 2017-09-29 | 大连工业大学 | 一种海参加热过程中质构品质无损检测方法 |
AU2017230091B2 (en) | 2016-03-10 | 2022-04-07 | Acceleron Pharma Inc. | Activin type 2 receptor binding proteins and uses thereof |
HRP20230308T1 (hr) | 2017-01-06 | 2023-05-12 | Scholar Rock, Inc. | Liječenje metaboličkih bolesti putem inhibiranja aktivacije miostatina |
HUE056694T2 (hu) | 2017-04-13 | 2022-03-28 | N R Soos Tech Ltd | Berendezések és eljárások nõstény embriók termelésének elõsegítésére tojásokban |
KR101822633B1 (ko) * | 2017-08-22 | 2018-01-26 | (주)진셀팜 | 폴리스타틴 유래 생리활성 펩타이드, 및 이의 용도 |
EP3694552A1 (en) | 2017-10-10 | 2020-08-19 | Tilos Therapeutics, Inc. | Anti-lap antibodies and uses thereof |
EP3732287A1 (en) * | 2017-12-29 | 2020-11-04 | Anagenesis Biotechnologies Sas | Method for preparing bap or ba cells |
CN109006709A (zh) * | 2018-08-17 | 2018-12-18 | 孟维巍 | 一种紧凑式蜚蠊养殖系统 |
EP3863722A2 (en) | 2018-10-10 | 2021-08-18 | Tilos Theapeutics, Inc. | Anti-lap antibody variants and uses thereof |
US20220143136A1 (en) | 2018-12-21 | 2022-05-12 | Northwestern University | Use of annexins in preventing and treating muscle membrane injury |
US20220062299A1 (en) | 2018-12-26 | 2022-03-03 | Northwestern University | Use of glucocorticoid steroids in preventing and treating conditions of muscle wasting, aging and metabolic disorder |
CN110438154A (zh) * | 2019-08-10 | 2019-11-12 | 湖南文理学院 | 一种基于转基因增加鲫鱼生长速度的方法 |
CN112088804B (zh) * | 2020-10-13 | 2021-12-21 | 四川省旺达饲料有限公司 | 一种根据家禽体型自动定量出料的饲料投喂装置 |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998023284A1 (en) * | 1996-11-27 | 1998-06-04 | Immunex Corporation | Method of regulating nitric oxide production |
WO1998052038A1 (en) * | 1997-05-16 | 1998-11-19 | The Procter & Gamble Company | The use of a bone morphogenetic protein (bmp) receptor complex for screening |
WO1998053838A2 (en) * | 1997-05-30 | 1998-12-03 | Winnacker Ernst Ludwig | A soluble laminin receptor precursor and methods to inhibit its interactions |
WO1999058674A2 (en) * | 1998-05-14 | 1999-11-18 | Immunex Corporation | Method of inhibiting osteoclast activity |
WO2000043781A2 (en) * | 1999-01-21 | 2000-07-27 | Metamorphix, Inc. | Growth differentiation factor inhibitors and uses therefor |
Family Cites Families (52)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4036945A (en) | 1976-05-03 | 1977-07-19 | The Massachusetts General Hospital | Composition and method for determining the size and location of myocardial infarcts |
US4331647A (en) | 1980-03-03 | 1982-05-25 | Goldenberg Milton David | Tumor localization and therapy with labeled antibody fragments specific to tumor-associated markers |
US4873191A (en) | 1981-06-12 | 1989-10-10 | Ohio University | Genetic transformation of zygotes |
US5206347A (en) | 1985-08-06 | 1993-04-27 | La Jolla Cancer Research Foundation | Isolation and use of receptors binding to a peptide column |
US4946778A (en) | 1987-09-21 | 1990-08-07 | Genex Corporation | Single polypeptide chain binding molecules |
US5011912A (en) | 1986-12-19 | 1991-04-30 | Immunex Corporation | Hybridoma and monoclonal antibody for use in an immunoaffinity purification system |
US5162215A (en) | 1988-09-22 | 1992-11-10 | Amgen Inc. | Method of gene transfer into chickens and other avian species |
US5399346A (en) | 1989-06-14 | 1995-03-21 | The United States Of America As Represented By The Department Of Health And Human Services | Gene therapy |
US6218596B1 (en) | 1989-06-30 | 2001-04-17 | The United States Of America As Represented By The Department Of Health And Human Services | Enhancement of musculature in non-human mammals expressing c-ski |
US5225212A (en) | 1989-10-20 | 1993-07-06 | Liposome Technology, Inc. | Microreservoir liposome composition and method |
US5633076A (en) | 1989-12-01 | 1997-05-27 | Pharming Bv | Method of producing a transgenic bovine or transgenic bovine embryo |
US5283173A (en) | 1990-01-24 | 1994-02-01 | The Research Foundation Of State University Of New York | System to detect protein-protein interactions |
EP0438803B1 (en) | 1990-01-26 | 1997-03-12 | Immunomedics, Inc. | Vaccines against cancer and infectious diseases |
US5265030A (en) | 1990-04-24 | 1993-11-23 | Scripps Clinic And Research Foundation | System and method for determining three-dimensional structures of proteins |
US5750342A (en) | 1990-06-11 | 1998-05-12 | Nexstar Pharmaceuticals, Inc. | Nucleic acid ligands of tissue target |
US5264563A (en) | 1990-08-24 | 1993-11-23 | Ixsys Inc. | Process for synthesizing oligonucleotides with random codons |
US5314695A (en) | 1990-11-13 | 1994-05-24 | Corvas International, Inc. | Tissue factor based prothrombin time reagent |
US6162896A (en) * | 1991-05-10 | 2000-12-19 | The Salk Institute For Biological Studies | Recombinant vertebrate activin receptors |
US5885794A (en) | 1991-05-10 | 1999-03-23 | The Salk Institute For Biological Studies | Recombinant production of vertebrate activin receptor polypeptides and identification of receptor DNAs in the activin/TGF-β superfamily |
WO1993001484A1 (en) | 1991-07-11 | 1993-01-21 | The Regents Of The University Of California | A method to identify protein sequences that fold into a known three-dimensional structure |
US5395619A (en) | 1993-03-03 | 1995-03-07 | Liposome Technology, Inc. | Lipid-polymer conjugates and liposomes |
US5994618A (en) | 1997-02-05 | 1999-11-30 | Johns Hopkins University School Of Medicine | Growth differentiation factor-8 transgenic mice |
WO1994021681A1 (en) * | 1993-03-19 | 1994-09-29 | Johns Hopkins University School Of Medicine | Growth differentiation factor-8 |
US6465239B1 (en) | 1993-03-19 | 2002-10-15 | The John Hopkins University School Of Medicine | Growth differentiation factor-8 nucleic acid and polypeptides from aquatic species and non-human transgenic aquatic species |
WO1994026892A1 (en) * | 1993-05-12 | 1994-11-24 | Genetics Institute, Inc. | Bmp-11 compositions |
US6008434A (en) | 1994-07-08 | 1999-12-28 | Johns Hopkins University School Of Medicine | Growth differentiation factor-11 transgenic mice |
WO1996001845A1 (en) * | 1994-07-08 | 1996-01-25 | The Johns Hopkins University School Of Medicine | Growth differentiation factor-11 |
US5734039A (en) | 1994-09-15 | 1998-03-31 | Thomas Jefferson University | Antisense oligonucleotides targeting cooperating oncogenes |
US5545616A (en) * | 1994-09-22 | 1996-08-13 | Genentech, Inc. | Method for predicting and/or preventing preterm labor |
US5998698A (en) | 1995-06-07 | 1999-12-07 | Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College | Transgenic fish capable of expressing exogenous lytic peptides |
US5622699A (en) | 1995-09-11 | 1997-04-22 | La Jolla Cancer Research Foundation | Method of identifying molecules that home to a selected organ in vivo |
WO1997015319A1 (en) * | 1995-10-23 | 1997-05-01 | Queen's University At Kingston | Method and pharmaceutical composition for chondrostimulation with a prostaglandin (e.g. misoprostol) and tgf-beta, optionally in combination with igf-1 |
DE19626982C1 (de) | 1996-07-04 | 1997-09-25 | Siemens Ag | Elektromagnetisches Relais und Verfahren zu dessen Herstellung |
US5776689A (en) | 1996-07-19 | 1998-07-07 | The Regents Of The University Of California | Protein recruitment system |
AU6274298A (en) | 1997-02-05 | 1998-08-25 | Johns Hopkins University School Of Medicine, The | Growth differentiation factor-8 |
US5827533A (en) | 1997-02-06 | 1998-10-27 | Duke University | Liposomes containing active agents aggregated with lipid surfactants |
US5933819C1 (en) | 1997-05-23 | 2001-11-13 | Scripps Research Inst | Prediction of relative binding motifs of biologically active peptides and peptide mimetics |
DE69838334T2 (de) * | 1997-06-18 | 2008-06-12 | Merck & Co., Inc. (A New Jersey Corp.) | Kdr, ein menschlicher tyrosin kinase rezeptor |
WO1999006559A1 (en) | 1997-08-01 | 1999-02-11 | The Johns Hopkins University School Of Medicine | Methods to identify growth differentiation factor (gdf) receptors |
US6891082B2 (en) | 1997-08-01 | 2005-05-10 | The Johns Hopkins University School Of Medicine | Transgenic non-human animals expressing a truncated activintype II receptor |
US6656475B1 (en) * | 1997-08-01 | 2003-12-02 | The Johns Hopkins University School Of Medicine | Growth differentiation factor receptors, agonists and antagonists thereof, and methods of using same |
CA2302780A1 (en) * | 1997-08-29 | 1999-03-04 | Ontogeny, Inc. | Regulation of muscle tissues by hedgehog-like polypeptides, and formulations and uses related thereto |
JP2001513982A (ja) * | 1997-08-29 | 2001-09-11 | ヒューマン ジノーム サイエンシーズ, インコーポレイテッド | フォリスタチン−3 |
US5885779A (en) | 1997-09-09 | 1999-03-23 | University Of British Columbia | Repressed trans-activator system for characterization of protein-protein interactions |
AU2586199A (en) | 1998-02-05 | 1999-08-23 | Johns Hopkins University School Of Medicine, The | Growth differentiation factor-8 |
US6004937A (en) * | 1998-03-09 | 1999-12-21 | Genetics Institute, Inc. | Use of follistatin to modulate growth and differentiation factor 8 [GDF-8] and bone morphogenic protein 11 [BMP-11] |
US6156952A (en) * | 1998-04-09 | 2000-12-05 | Constituent Institution Of The University Of Maryland System | HIV transgenic animals and uses therefor |
JP4544742B2 (ja) | 1998-05-06 | 2010-09-15 | メタモーフイクス・インコーポレーテツド | Gdf−8の阻害による糖尿病の処置法 |
AU1177700A (en) | 1998-11-13 | 2000-06-05 | Takeda Chemical Industries Ltd. | Novel protein and utilization thereof |
AU5474400A (en) | 1999-06-08 | 2000-12-28 | Rutgers, The State University | Compositions and methods for targeted gene insertion |
AU782925B2 (en) | 2000-01-18 | 2005-09-08 | Orico Limited | Myostatin and mimetics thereof |
TWI782836B (zh) * | 2007-02-02 | 2022-11-01 | 美商艾瑟勒朗法瑪公司 | 衍生自ActRIIB的變體與其用途 |
-
2001
- 2001-04-24 US US09/841,730 patent/US6891082B2/en not_active Expired - Fee Related
-
2002
- 2002-04-24 PL PL02367201A patent/PL367201A1/xx unknown
- 2002-04-24 JP JP2002582882A patent/JP2004537982A/ja active Pending
- 2002-04-24 KR KR1020097005537A patent/KR20090032148A/ko not_active Application Discontinuation
- 2002-04-24 AU AU2002307564A patent/AU2002307564B2/en not_active Ceased
- 2002-04-24 EP EP02764345A patent/EP1395113A4/en not_active Withdrawn
- 2002-04-24 HU HU0401542A patent/HUP0401542A2/hu unknown
- 2002-04-24 CN CN028126106A patent/CN1520256B/zh not_active Expired - Lifetime
- 2002-04-24 WO PCT/US2002/013103 patent/WO2002085306A2/en active Application Filing
- 2002-04-24 BR BR0209191-7A patent/BR0209191A/pt not_active IP Right Cessation
- 2002-04-24 CA CA2807478A patent/CA2807478A1/en not_active Abandoned
- 2002-04-24 CA CA2448835A patent/CA2448835C/en not_active Expired - Fee Related
- 2002-04-24 KR KR1020087012173A patent/KR20080051190A/ko active IP Right Grant
- 2002-04-24 NZ NZ528963A patent/NZ528963A/en unknown
- 2002-04-24 IL IL15842002A patent/IL158420A0/xx unknown
- 2002-04-24 EP EP10183805A patent/EP2340709A1/en not_active Withdrawn
- 2002-04-24 KR KR10-2003-7013983A patent/KR20040002927A/ko active IP Right Grant
-
2003
- 2003-10-15 IL IL158420A patent/IL158420A/en not_active IP Right Cessation
- 2003-10-15 ZA ZA200308021A patent/ZA200308021B/en unknown
- 2003-10-20 NO NO20034693A patent/NO20034693L/no not_active Application Discontinuation
-
2005
- 2005-02-03 US US11/051,267 patent/US20050257278A1/en not_active Abandoned
-
2008
- 2008-04-25 JP JP2008116224A patent/JP4361955B2/ja not_active Expired - Fee Related
- 2008-11-21 JP JP2008298119A patent/JP5004930B2/ja not_active Expired - Fee Related
-
2009
- 2009-01-26 US US12/360,093 patent/US20090186806A1/en not_active Abandoned
- 2009-01-28 US US12/361,512 patent/US8124830B2/en not_active Expired - Fee Related
- 2009-06-22 JP JP2009147316A patent/JP5425537B2/ja not_active Expired - Fee Related
-
2010
- 2010-08-23 US US12/861,738 patent/US8822411B2/en not_active Expired - Fee Related
- 2010-10-04 US US12/897,607 patent/US20120094908A1/en not_active Abandoned
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998023284A1 (en) * | 1996-11-27 | 1998-06-04 | Immunex Corporation | Method of regulating nitric oxide production |
WO1998052038A1 (en) * | 1997-05-16 | 1998-11-19 | The Procter & Gamble Company | The use of a bone morphogenetic protein (bmp) receptor complex for screening |
WO1998053838A2 (en) * | 1997-05-30 | 1998-12-03 | Winnacker Ernst Ludwig | A soluble laminin receptor precursor and methods to inhibit its interactions |
WO1999058674A2 (en) * | 1998-05-14 | 1999-11-18 | Immunex Corporation | Method of inhibiting osteoclast activity |
WO2000043781A2 (en) * | 1999-01-21 | 2000-07-27 | Metamorphix, Inc. | Growth differentiation factor inhibitors and uses therefor |
Non-Patent Citations (1)
Title |
---|
JPN6012016328; Int.J.Cancer, vol.77, pp.860-868 (1998) * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2323133A2 (en) | 2009-11-16 | 2011-05-18 | Sony Corporation | Disc cartridge |
JP2012067081A (ja) * | 2010-08-24 | 2012-04-05 | Okayama Univ | 疼痛の治療剤 |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP4361955B2 (ja) | 筋重量を増加させるためのフォリスタチンの使用方法 | |
JP5785525B2 (ja) | 増殖分化因子受容体、そのアゴニスト、およびアンタゴニスト、ならびにそれらの使用方法 | |
JP5149478B2 (ja) | プロミオスタチンペプチドおよびその使用法 | |
AU2002307564A1 (en) | Use of follistatin to increase muscle mass | |
AU2001282999A1 (en) | Growth differentiation factor receptors, agonists and antagonists thereof, and methods of using same | |
AU2012204098B2 (en) | Use of follistatin to increase muscle mass | |
US7566768B1 (en) | Promyostatin peptides and methods of using same | |
AU2007200633B2 (en) | Growth differentiation factor receptors, agonists and antagonists thereof, and methods of using same | |
AU2007201968A1 (en) | Use of follistatin to increase muscle mass | |
AU2006209266A1 (en) | Promyostatin peptides and methods of using same | |
MXPA03009768A (es) | Uso de folistatina para incrementar la masa muscular |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20120328 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20120627 |
|
A602 | Written permission of extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A602 Effective date: 20120702 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20120725 |
|
A602 | Written permission of extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A602 Effective date: 20120730 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20120827 |
|
A602 | Written permission of extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A602 Effective date: 20120830 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20120910 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20130220 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20130520 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20131030 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20131127 |
|
R150 | Certificate of patent or registration of utility model |
Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
LAPS | Cancellation because of no payment of annual fees |