CN113956345A - Angpt4蛋白及其编码基因在调控心脏损伤后的修复与再生能力中的应用 - Google Patents
Angpt4蛋白及其编码基因在调控心脏损伤后的修复与再生能力中的应用 Download PDFInfo
- Publication number
- CN113956345A CN113956345A CN202111064028.8A CN202111064028A CN113956345A CN 113956345 A CN113956345 A CN 113956345A CN 202111064028 A CN202111064028 A CN 202111064028A CN 113956345 A CN113956345 A CN 113956345A
- Authority
- CN
- China
- Prior art keywords
- angpt4
- protein
- heart
- animal
- human
- 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
- 102100033402 Angiopoietin-4 Human genes 0.000 title claims abstract description 93
- 101000732676 Homo sapiens Angiopoietin-4 Proteins 0.000 title claims abstract description 92
- 108090000623 proteins and genes Proteins 0.000 title claims abstract description 66
- 230000008929 regeneration Effects 0.000 title claims abstract description 56
- 238000011069 regeneration method Methods 0.000 title claims abstract description 56
- 230000006378 damage Effects 0.000 title claims abstract description 43
- 230000008439 repair process Effects 0.000 title claims abstract description 29
- 230000033228 biological regulation Effects 0.000 title abstract description 8
- 241000282414 Homo sapiens Species 0.000 claims abstract description 41
- 230000000747 cardiac effect Effects 0.000 claims abstract description 28
- 241000124008 Mammalia Species 0.000 claims abstract description 15
- 230000001105 regulatory effect Effects 0.000 claims abstract description 15
- 239000003814 drug Substances 0.000 claims abstract description 12
- 230000001225 therapeutic effect Effects 0.000 claims abstract description 10
- 102000004169 proteins and genes Human genes 0.000 claims abstract description 9
- 230000001276 controlling effect Effects 0.000 claims abstract description 7
- 230000014509 gene expression Effects 0.000 claims description 48
- 210000004413 cardiac myocyte Anatomy 0.000 claims description 43
- 210000004027 cell Anatomy 0.000 claims description 43
- 241001465754 Metazoa Species 0.000 claims description 39
- 241000252212 Danio rerio Species 0.000 claims description 38
- 208000027418 Wounds and injury Diseases 0.000 claims description 27
- 208000013875 Heart injury Diseases 0.000 claims description 22
- 208000014674 injury Diseases 0.000 claims description 22
- 231100000241 scar Toxicity 0.000 claims description 20
- 230000002861 ventricular Effects 0.000 claims description 20
- 239000012620 biological material Substances 0.000 claims description 19
- 230000035755 proliferation Effects 0.000 claims description 17
- 201000010099 disease Diseases 0.000 claims description 15
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 15
- 239000013598 vector Substances 0.000 claims description 15
- 208000010125 myocardial infarction Diseases 0.000 claims description 14
- 230000003176 fibrotic effect Effects 0.000 claims description 12
- 230000003683 cardiac damage Effects 0.000 claims description 10
- 230000002401 inhibitory effect Effects 0.000 claims description 10
- 108020003175 receptors Proteins 0.000 claims description 9
- 102000005962 receptors Human genes 0.000 claims description 9
- 101100481410 Mus musculus Tek gene Proteins 0.000 claims description 8
- 239000003153 chemical reaction reagent Substances 0.000 claims description 8
- 239000003112 inhibitor Substances 0.000 claims description 8
- 101100481408 Danio rerio tie2 gene Proteins 0.000 claims description 7
- 238000000338 in vitro Methods 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 230000001737 promoting effect Effects 0.000 claims description 6
- 230000002265 prevention Effects 0.000 claims description 5
- 230000002062 proliferating effect Effects 0.000 claims description 5
- 125000000539 amino acid group Chemical group 0.000 claims description 4
- 230000000694 effects Effects 0.000 claims description 4
- 241000894006 Bacteria Species 0.000 claims description 3
- 102000008946 Fibrinogen Human genes 0.000 claims description 3
- 108010049003 Fibrinogen Proteins 0.000 claims description 3
- 206010028851 Necrosis Diseases 0.000 claims description 3
- 238000010171 animal model Methods 0.000 claims description 3
- 230000006907 apoptotic process Effects 0.000 claims description 3
- 210000004899 c-terminal region Anatomy 0.000 claims description 3
- 229940012952 fibrinogen Drugs 0.000 claims description 3
- 230000005764 inhibitory process Effects 0.000 claims description 3
- 230000017074 necrotic cell death Effects 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 241000282693 Cercopithecidae Species 0.000 claims description 2
- 241000251476 Chimaera monstrosa Species 0.000 claims description 2
- 241000203121 Orthopristis chrysoptera Species 0.000 claims description 2
- 241000288906 Primates Species 0.000 claims description 2
- 241000283984 Rodentia Species 0.000 claims description 2
- 241001493546 Suina Species 0.000 claims description 2
- 230000003213 activating effect Effects 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 claims description 2
- 230000007547 defect Effects 0.000 claims description 2
- 210000002889 endothelial cell Anatomy 0.000 claims description 2
- 230000008065 myocardial cell damage Effects 0.000 claims description 2
- 208000031225 myocardial ischemia Diseases 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 108091006082 receptor inhibitors Proteins 0.000 claims description 2
- 230000019491 signal transduction Effects 0.000 claims description 2
- 241000894007 species Species 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- 125000003275 alpha amino acid group Chemical group 0.000 claims 4
- 241000997865 Histrio histrio Species 0.000 claims 1
- 230000018109 developmental process Effects 0.000 abstract description 10
- 229940079593 drug Drugs 0.000 abstract description 4
- 230000009286 beneficial effect Effects 0.000 abstract description 3
- 208000024172 Cardiovascular disease Diseases 0.000 abstract description 2
- 238000012377 drug delivery Methods 0.000 abstract description 2
- 239000003446 ligand Substances 0.000 abstract description 2
- 238000011002 quantification Methods 0.000 abstract description 2
- 238000012827 research and development Methods 0.000 abstract description 2
- 230000028327 secretion Effects 0.000 abstract description 2
- 230000008685 targeting Effects 0.000 abstract description 2
- 241000699670 Mus sp. Species 0.000 description 15
- 230000002107 myocardial effect Effects 0.000 description 15
- 230000002018 overexpression Effects 0.000 description 14
- 210000001519 tissue Anatomy 0.000 description 14
- 238000010186 staining Methods 0.000 description 12
- 241000251468 Actinopterygii Species 0.000 description 11
- VAOCPAMSLUNLGC-UHFFFAOYSA-N metronidazole Chemical compound CC1=NC=C([N+]([O-])=O)N1CCO VAOCPAMSLUNLGC-UHFFFAOYSA-N 0.000 description 11
- 229960000282 metronidazole Drugs 0.000 description 11
- 210000001161 mammalian embryo Anatomy 0.000 description 10
- 241000699666 Mus <mouse, genus> Species 0.000 description 9
- 230000035772 mutation Effects 0.000 description 9
- 239000005441 aurora Substances 0.000 description 8
- 241000700159 Rattus Species 0.000 description 7
- 230000008859 change Effects 0.000 description 7
- 238000011161 development Methods 0.000 description 7
- 210000002257 embryonic structure Anatomy 0.000 description 7
- 230000006870 function Effects 0.000 description 7
- 230000008569 process Effects 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 150000001413 amino acids Chemical group 0.000 description 6
- 230000004217 heart function Effects 0.000 description 6
- 239000008267 milk Substances 0.000 description 6
- 235000013336 milk Nutrition 0.000 description 6
- 210000004080 milk Anatomy 0.000 description 6
- 230000009261 transgenic effect Effects 0.000 description 6
- 210000003315 endocardial cell Anatomy 0.000 description 5
- 108010048367 enhanced green fluorescent protein Proteins 0.000 description 5
- 238000011084 recovery Methods 0.000 description 5
- 238000001356 surgical procedure Methods 0.000 description 5
- 241000702421 Dependoparvovirus Species 0.000 description 4
- 101100148573 Rattus norvegicus S1pr5 gene Proteins 0.000 description 4
- 230000001746 atrial effect Effects 0.000 description 4
- 230000009067 heart development Effects 0.000 description 4
- 238000007901 in situ hybridization Methods 0.000 description 4
- 108020004999 messenger RNA Proteins 0.000 description 4
- 230000001172 regenerating effect Effects 0.000 description 4
- 101150034993 ANGPT4 gene Proteins 0.000 description 3
- 206010016654 Fibrosis Diseases 0.000 description 3
- 206010019280 Heart failures Diseases 0.000 description 3
- YBAFDPFAUTYYRW-UHFFFAOYSA-N N-L-alpha-glutamyl-L-leucine Natural products CC(C)CC(C(O)=O)NC(=O)C(N)CCC(O)=O YBAFDPFAUTYYRW-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000012217 deletion Methods 0.000 description 3
- 230000037430 deletion Effects 0.000 description 3
- 230000004761 fibrosis Effects 0.000 description 3
- 108010020688 glycylhistidine Proteins 0.000 description 3
- 210000002837 heart atrium Anatomy 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 239000003550 marker Substances 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 238000012163 sequencing technique Methods 0.000 description 3
- 238000007619 statistical method Methods 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 241000649044 Adeno-associated virus 9 Species 0.000 description 2
- OKZOABJQOMAYEC-NUMRIWBASA-N Asn-Gln-Thr Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O OKZOABJQOMAYEC-NUMRIWBASA-N 0.000 description 2
- QRULNKJGYQQZMW-ZLUOBGJFSA-N Asp-Asn-Asp Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O QRULNKJGYQQZMW-ZLUOBGJFSA-N 0.000 description 2
- 108091033409 CRISPR Proteins 0.000 description 2
- 101100342337 Caenorhabditis elegans klf-1 gene Proteins 0.000 description 2
- 108020004705 Codon Proteins 0.000 description 2
- FKXCBKCOSVIGCT-AVGNSLFASA-N Gln-Lys-Leu Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(O)=O FKXCBKCOSVIGCT-AVGNSLFASA-N 0.000 description 2
- BCYGDJXHAGZNPQ-DCAQKATOSA-N Glu-Lys-Glu Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(O)=O BCYGDJXHAGZNPQ-DCAQKATOSA-N 0.000 description 2
- 108020005004 Guide RNA Proteins 0.000 description 2
- OQDLKDUVMTUPPG-AVGNSLFASA-N His-Leu-Glu Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O OQDLKDUVMTUPPG-AVGNSLFASA-N 0.000 description 2
- DMHGKBGOUAJRHU-UHFFFAOYSA-N Ile-Arg-Pro Natural products CCC(C)C(N)C(=O)NC(CCCN=C(N)N)C(=O)N1CCCC1C(O)=O DMHGKBGOUAJRHU-UHFFFAOYSA-N 0.000 description 2
- PMGDADKJMCOXHX-UHFFFAOYSA-N L-Arginyl-L-glutamin-acetat Natural products NC(=N)NCCCC(N)C(=O)NC(CCC(N)=O)C(O)=O PMGDADKJMCOXHX-UHFFFAOYSA-N 0.000 description 2
- 241000880493 Leptailurus serval Species 0.000 description 2
- VPKIQULSKFVCSM-SRVKXCTJSA-N Leu-Gln-Arg Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O VPKIQULSKFVCSM-SRVKXCTJSA-N 0.000 description 2
- YVKSMSDXKMSIRX-GUBZILKMSA-N Leu-Glu-Asn Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O YVKSMSDXKMSIRX-GUBZILKMSA-N 0.000 description 2
- KVMULWOHPPMHHE-DCAQKATOSA-N Leu-Glu-Gln Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O KVMULWOHPPMHHE-DCAQKATOSA-N 0.000 description 2
- AEQVPPGEJJBFEE-CYDGBPFRSA-N Met-Ile-Arg Chemical compound CSCC[C@H](N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O AEQVPPGEJJBFEE-CYDGBPFRSA-N 0.000 description 2
- AJHCSUXXECOXOY-UHFFFAOYSA-N N-glycyl-L-tryptophan Natural products C1=CC=C2C(CC(NC(=O)CN)C(O)=O)=CNC2=C1 AJHCSUXXECOXOY-UHFFFAOYSA-N 0.000 description 2
- 102000048238 Neuregulin-1 Human genes 0.000 description 2
- 108090000556 Neuregulin-1 Proteins 0.000 description 2
- JEBWZLWTRPZQRX-QWRGUYRKSA-N Phe-Gly-Asp Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(O)=O JEBWZLWTRPZQRX-QWRGUYRKSA-N 0.000 description 2
- IAOZOFPONWDXNT-IXOXFDKPSA-N Phe-Ser-Thr Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(O)=O IAOZOFPONWDXNT-IXOXFDKPSA-N 0.000 description 2
- 235000011609 Pinus massoniana Nutrition 0.000 description 2
- 241000018650 Pinus massoniana Species 0.000 description 2
- HRNQLKCLPVKZNE-CIUDSAMLSA-N Ser-Ala-Leu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(O)=O HRNQLKCLPVKZNE-CIUDSAMLSA-N 0.000 description 2
- SRSPTFBENMJHMR-WHFBIAKZSA-N Ser-Ser-Gly Chemical compound OC[C@H](N)C(=O)N[C@@H](CO)C(=O)NCC(O)=O SRSPTFBENMJHMR-WHFBIAKZSA-N 0.000 description 2
- FLPZMPOZGYPBEN-PPCPHDFISA-N Thr-Leu-Ile Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O FLPZMPOZGYPBEN-PPCPHDFISA-N 0.000 description 2
- WNQJTLATMXYSEL-OEAJRASXSA-N Thr-Phe-Leu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(C)C)C(O)=O WNQJTLATMXYSEL-OEAJRASXSA-N 0.000 description 2
- AOLQJUGGZLTUBD-WIRXVTQYSA-N Trp-Trp-Phe Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O AOLQJUGGZLTUBD-WIRXVTQYSA-N 0.000 description 2
- QGFPYRPIUXBYGR-YDHLFZDLSA-N Val-Asn-Phe Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)N QGFPYRPIUXBYGR-YDHLFZDLSA-N 0.000 description 2
- YQMILNREHKTFBS-IHRRRGAJSA-N Val-Phe-Cys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CS)C(=O)O)N YQMILNREHKTFBS-IHRRRGAJSA-N 0.000 description 2
- 241000700605 Viruses Species 0.000 description 2
- 108010044940 alanylglutamine Proteins 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 108010069801 angiopoietin 4 Proteins 0.000 description 2
- 108010008355 arginyl-glutamine Proteins 0.000 description 2
- 108010062796 arginyllysine Proteins 0.000 description 2
- 108010093581 aspartyl-proline Proteins 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 230000003205 diastolic effect Effects 0.000 description 2
- 235000013601 eggs Nutrition 0.000 description 2
- 230000037433 frameshift Effects 0.000 description 2
- 238000001415 gene therapy Methods 0.000 description 2
- 108010049041 glutamylalanine Proteins 0.000 description 2
- 108010089804 glycyl-threonine Proteins 0.000 description 2
- 108010084389 glycyltryptophan Proteins 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 230000003834 intracellular effect Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 210000004165 myocardium Anatomy 0.000 description 2
- DHRLEVQXOMLTIM-UHFFFAOYSA-N phosphoric acid;trioxomolybdenum Chemical compound O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.OP(O)(O)=O DHRLEVQXOMLTIM-UHFFFAOYSA-N 0.000 description 2
- 238000003753 real-time PCR Methods 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 108010048397 seryl-lysyl-leucine Proteins 0.000 description 2
- 210000000130 stem cell Anatomy 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- 238000012795 verification Methods 0.000 description 2
- QMOQBVOBWVNSNO-UHFFFAOYSA-N 2-[[2-[[2-[(2-azaniumylacetyl)amino]acetyl]amino]acetyl]amino]acetate Chemical compound NCC(=O)NCC(=O)NCC(=O)NCC(O)=O QMOQBVOBWVNSNO-UHFFFAOYSA-N 0.000 description 1
- 102000007469 Actins Human genes 0.000 description 1
- 108010085238 Actins Proteins 0.000 description 1
- YYSWCHMLFJLLBJ-ZLUOBGJFSA-N Ala-Ala-Ser Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(O)=O YYSWCHMLFJLLBJ-ZLUOBGJFSA-N 0.000 description 1
- YAXNATKKPOWVCP-ZLUOBGJFSA-N Ala-Asn-Ala Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(O)=O YAXNATKKPOWVCP-ZLUOBGJFSA-N 0.000 description 1
- XCVRVWZTXPCYJT-BIIVOSGPSA-N Ala-Asn-Pro Chemical compound C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N1CCC[C@@H]1C(=O)O)N XCVRVWZTXPCYJT-BIIVOSGPSA-N 0.000 description 1
- PBAMJJXWDQXOJA-FXQIFTODSA-N Ala-Asp-Arg Chemical compound C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CCCN=C(N)N PBAMJJXWDQXOJA-FXQIFTODSA-N 0.000 description 1
- KRHRBKYBJXMYBB-WHFBIAKZSA-N Ala-Cys-Gly Chemical compound C[C@H](N)C(=O)N[C@@H](CS)C(=O)NCC(O)=O KRHRBKYBJXMYBB-WHFBIAKZSA-N 0.000 description 1
- BLGHHPHXVJWCNK-GUBZILKMSA-N Ala-Gln-Leu Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(O)=O BLGHHPHXVJWCNK-GUBZILKMSA-N 0.000 description 1
- YIGLXQRFQVWFEY-NRPADANISA-N Ala-Gln-Val Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(O)=O YIGLXQRFQVWFEY-NRPADANISA-N 0.000 description 1
- FUSPCLTUKXQREV-ACZMJKKPSA-N Ala-Glu-Ala Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(O)=O FUSPCLTUKXQREV-ACZMJKKPSA-N 0.000 description 1
- GGNHBHYDMUDXQB-KBIXCLLPSA-N Ala-Glu-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)N GGNHBHYDMUDXQB-KBIXCLLPSA-N 0.000 description 1
- WGDNWOMKBUXFHR-BQBZGAKWSA-N Ala-Gly-Arg Chemical compound C[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CCCN=C(N)N WGDNWOMKBUXFHR-BQBZGAKWSA-N 0.000 description 1
- NMXKFWOEASXOGB-QSFUFRPTSA-N Ala-Ile-His Chemical compound C[C@H](N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@H](C(O)=O)CC1=CN=CN1 NMXKFWOEASXOGB-QSFUFRPTSA-N 0.000 description 1
- RZZMZYZXNJRPOJ-BJDJZHNGSA-N Ala-Ile-Lys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](C)N RZZMZYZXNJRPOJ-BJDJZHNGSA-N 0.000 description 1
- LXAARTARZJJCMB-CIQUZCHMSA-N Ala-Ile-Thr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(O)=O LXAARTARZJJCMB-CIQUZCHMSA-N 0.000 description 1
- HHRAXZAYZFFRAM-CIUDSAMLSA-N Ala-Leu-Asn Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O HHRAXZAYZFFRAM-CIUDSAMLSA-N 0.000 description 1
- SUMYEVXWCAYLLJ-GUBZILKMSA-N Ala-Leu-Gln Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O SUMYEVXWCAYLLJ-GUBZILKMSA-N 0.000 description 1
- CCDFBRZVTDDJNM-GUBZILKMSA-N Ala-Leu-Glu Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O CCDFBRZVTDDJNM-GUBZILKMSA-N 0.000 description 1
- RGQCNKIDEQJEBT-CQDKDKBSSA-N Ala-Leu-Tyr Chemical compound C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 RGQCNKIDEQJEBT-CQDKDKBSSA-N 0.000 description 1
- PMQXMXAASGFUDX-SRVKXCTJSA-N Ala-Lys-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@H](C)N)CCCCN PMQXMXAASGFUDX-SRVKXCTJSA-N 0.000 description 1
- MDNAVFBZPROEHO-UHFFFAOYSA-N Ala-Lys-Val Natural products CC(C)C(C(O)=O)NC(=O)C(NC(=O)C(C)N)CCCCN MDNAVFBZPROEHO-UHFFFAOYSA-N 0.000 description 1
- RUXQNKVQSKOOBS-JURCDPSOSA-N Ala-Phe-Ile Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O RUXQNKVQSKOOBS-JURCDPSOSA-N 0.000 description 1
- BHTBAVZSZCQZPT-GUBZILKMSA-N Ala-Pro-Met Chemical compound CSCC[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H](C)N BHTBAVZSZCQZPT-GUBZILKMSA-N 0.000 description 1
- VJVQKGYHIZPSNS-FXQIFTODSA-N Ala-Ser-Arg Chemical compound C[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CCCN=C(N)N VJVQKGYHIZPSNS-FXQIFTODSA-N 0.000 description 1
- RTZCUEHYUQZIDE-WHFBIAKZSA-N Ala-Ser-Gly Chemical compound C[C@H](N)C(=O)N[C@@H](CO)C(=O)NCC(O)=O RTZCUEHYUQZIDE-WHFBIAKZSA-N 0.000 description 1
- ISCYZXFOCXWUJU-KZVJFYERSA-N Ala-Thr-Met Chemical compound [H]N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCSC)C(O)=O ISCYZXFOCXWUJU-KZVJFYERSA-N 0.000 description 1
- CLOMBHBBUKAUBP-LSJOCFKGSA-N Ala-Val-His Chemical compound C[C@@H](C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N CLOMBHBBUKAUBP-LSJOCFKGSA-N 0.000 description 1
- RWCLSUOSKWTXLA-FXQIFTODSA-N Arg-Asp-Ala Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(O)=O RWCLSUOSKWTXLA-FXQIFTODSA-N 0.000 description 1
- RCAUJZASOAFTAJ-FXQIFTODSA-N Arg-Asp-Cys Chemical compound C(C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CS)C(=O)O)N)CN=C(N)N RCAUJZASOAFTAJ-FXQIFTODSA-N 0.000 description 1
- HKRXJBBCQBAGIM-FXQIFTODSA-N Arg-Asp-Ser Chemical compound C(C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CO)C(=O)O)N)CN=C(N)N HKRXJBBCQBAGIM-FXQIFTODSA-N 0.000 description 1
- VDBKFYYIBLXEIF-GUBZILKMSA-N Arg-Gln-Glu Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O VDBKFYYIBLXEIF-GUBZILKMSA-N 0.000 description 1
- VNFWDYWTSHFRRG-SRVKXCTJSA-N Arg-Gln-Leu Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(O)=O VNFWDYWTSHFRRG-SRVKXCTJSA-N 0.000 description 1
- YHQGEARSFILVHL-HJGDQZAQSA-N Arg-Gln-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CCCN=C(N)N)N)O YHQGEARSFILVHL-HJGDQZAQSA-N 0.000 description 1
- UBCPNBUIQNMDNH-NAKRPEOUSA-N Arg-Ile-Ala Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(O)=O UBCPNBUIQNMDNH-NAKRPEOUSA-N 0.000 description 1
- GMFAGHNRXPSSJS-SRVKXCTJSA-N Arg-Leu-Gln Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O GMFAGHNRXPSSJS-SRVKXCTJSA-N 0.000 description 1
- COXMUHNBYCVVRG-DCAQKATOSA-N Arg-Leu-Ser Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O COXMUHNBYCVVRG-DCAQKATOSA-N 0.000 description 1
- CLICCYPMVFGUOF-IHRRRGAJSA-N Arg-Lys-Leu Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(O)=O CLICCYPMVFGUOF-IHRRRGAJSA-N 0.000 description 1
- JOTRDIXZHNQYGP-DCAQKATOSA-N Arg-Ser-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CCCN=C(N)N)N JOTRDIXZHNQYGP-DCAQKATOSA-N 0.000 description 1
- AUZAXCPWMDBWEE-HJGDQZAQSA-N Arg-Thr-Glu Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(O)=O)C(O)=O AUZAXCPWMDBWEE-HJGDQZAQSA-N 0.000 description 1
- ULBHWNVWSCJLCO-NHCYSSNCSA-N Arg-Val-Glu Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CCCN=C(N)N ULBHWNVWSCJLCO-NHCYSSNCSA-N 0.000 description 1
- IARGXWMWRFOQPG-GCJQMDKQSA-N Asn-Ala-Thr Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O IARGXWMWRFOQPG-GCJQMDKQSA-N 0.000 description 1
- VKCOHFFSTKCXEQ-OLHMAJIHSA-N Asn-Asn-Thr Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O VKCOHFFSTKCXEQ-OLHMAJIHSA-N 0.000 description 1
- CTQIOCMSIJATNX-WHFBIAKZSA-N Asn-Gly-Ala Chemical compound [H]N[C@@H](CC(N)=O)C(=O)NCC(=O)N[C@@H](C)C(O)=O CTQIOCMSIJATNX-WHFBIAKZSA-N 0.000 description 1
- FTCGGKNCJZOPNB-WHFBIAKZSA-N Asn-Gly-Ser Chemical compound NC(=O)C[C@H](N)C(=O)NCC(=O)N[C@@H](CO)C(O)=O FTCGGKNCJZOPNB-WHFBIAKZSA-N 0.000 description 1
- RAQMSGVCGSJKCL-FOHZUACHSA-N Asn-Gly-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CC(N)=O RAQMSGVCGSJKCL-FOHZUACHSA-N 0.000 description 1
- OLISTMZJGQUOGS-GMOBBJLQSA-N Asn-Ile-Arg Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)NC(=O)[C@H](CC(=O)N)N OLISTMZJGQUOGS-GMOBBJLQSA-N 0.000 description 1
- ZMUQQMGITUJQTI-CIUDSAMLSA-N Asn-Leu-Asn Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O ZMUQQMGITUJQTI-CIUDSAMLSA-N 0.000 description 1
- SNYCNNPOFYBCEK-ZLUOBGJFSA-N Asn-Ser-Ser Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O SNYCNNPOFYBCEK-ZLUOBGJFSA-N 0.000 description 1
- QUMKPKWYDVMGNT-NUMRIWBASA-N Asn-Thr-Gln Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CC(=O)N)N)O QUMKPKWYDVMGNT-NUMRIWBASA-N 0.000 description 1
- JBDLMLZNDRLDIX-HJGDQZAQSA-N Asn-Thr-Leu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O JBDLMLZNDRLDIX-HJGDQZAQSA-N 0.000 description 1
- AMGQTNHANMRPOE-LKXGYXEUSA-N Asn-Thr-Ser Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(O)=O AMGQTNHANMRPOE-LKXGYXEUSA-N 0.000 description 1
- GBAWQWASNGUNQF-ZLUOBGJFSA-N Asp-Ala-Cys Chemical compound C[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CC(=O)O)N GBAWQWASNGUNQF-ZLUOBGJFSA-N 0.000 description 1
- VTYQAQFKMQTKQD-ACZMJKKPSA-N Asp-Ala-Gln Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(O)=O VTYQAQFKMQTKQD-ACZMJKKPSA-N 0.000 description 1
- JDHOJQJMWBKHDB-CIUDSAMLSA-N Asp-Asn-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CC(=O)O)N JDHOJQJMWBKHDB-CIUDSAMLSA-N 0.000 description 1
- LJRPYAZQQWHEEV-FXQIFTODSA-N Asp-Gln-Gln Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O LJRPYAZQQWHEEV-FXQIFTODSA-N 0.000 description 1
- PSLSTUMPZILTAH-BYULHYEWSA-N Asp-Gly-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CC(O)=O PSLSTUMPZILTAH-BYULHYEWSA-N 0.000 description 1
- XLILXFRAKOYEJX-GUBZILKMSA-N Asp-Leu-Gln Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O XLILXFRAKOYEJX-GUBZILKMSA-N 0.000 description 1
- YWLDTBBUHZJQHW-KKUMJFAQSA-N Asp-Lys-Phe Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC(=O)O)N YWLDTBBUHZJQHW-KKUMJFAQSA-N 0.000 description 1
- JXGJJQJHXHXJQF-CIUDSAMLSA-N Asp-Met-Glu Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(O)=O JXGJJQJHXHXJQF-CIUDSAMLSA-N 0.000 description 1
- DJCAHYVLMSRBFR-QXEWZRGKSA-N Asp-Met-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H](CCSC)NC(=O)[C@@H](N)CC(O)=O DJCAHYVLMSRBFR-QXEWZRGKSA-N 0.000 description 1
- 238000010354 CRISPR gene editing Methods 0.000 description 1
- 206010011084 Coronary artery embolism Diseases 0.000 description 1
- 241000252206 Cypriniformes Species 0.000 description 1
- BCSYBBMFGLHCOA-ACZMJKKPSA-N Cys-Glu-Cys Chemical compound SC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CS)C(O)=O BCSYBBMFGLHCOA-ACZMJKKPSA-N 0.000 description 1
- BDWIZLQVVWQMTB-XKBZYTNZSA-N Cys-Glu-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CS)N)O BDWIZLQVVWQMTB-XKBZYTNZSA-N 0.000 description 1
- VDUPGIDTWNQAJD-CIUDSAMLSA-N Cys-Lys-Cys Chemical compound NCCCC[C@H](NC(=O)[C@@H](N)CS)C(=O)N[C@@H](CS)C(O)=O VDUPGIDTWNQAJD-CIUDSAMLSA-N 0.000 description 1
- KSMSFCBQBQPFAD-GUBZILKMSA-N Cys-Pro-Pro Chemical compound SC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(O)=O)CCC1 KSMSFCBQBQPFAD-GUBZILKMSA-N 0.000 description 1
- IXPSSIBVVKSOIE-SRVKXCTJSA-N Cys-Ser-Tyr Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CS)N)O IXPSSIBVVKSOIE-SRVKXCTJSA-N 0.000 description 1
- 108020004414 DNA Proteins 0.000 description 1
- REJJNXODKSHOKA-ACZMJKKPSA-N Gln-Ala-Asp Chemical compound C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)O)NC(=O)[C@H](CCC(=O)N)N REJJNXODKSHOKA-ACZMJKKPSA-N 0.000 description 1
- KWUSGAIFNHQCBY-DCAQKATOSA-N Gln-Arg-Arg Chemical compound NC(=O)CC[C@H](N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O KWUSGAIFNHQCBY-DCAQKATOSA-N 0.000 description 1
- DLOHWQXXGMEZDW-CIUDSAMLSA-N Gln-Arg-Asn Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(N)=O)C(O)=O DLOHWQXXGMEZDW-CIUDSAMLSA-N 0.000 description 1
- ZFADFBPRMSBPOT-KKUMJFAQSA-N Gln-Arg-Phe Chemical compound N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](Cc1ccccc1)C(O)=O ZFADFBPRMSBPOT-KKUMJFAQSA-N 0.000 description 1
- JESJDAAGXULQOP-CIUDSAMLSA-N Gln-Arg-Ser Chemical compound C(C[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CCC(=O)N)N)CN=C(N)N JESJDAAGXULQOP-CIUDSAMLSA-N 0.000 description 1
- TWHDOEYLXXQYOZ-FXQIFTODSA-N Gln-Asn-Gln Chemical compound C(CC(=O)N)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N TWHDOEYLXXQYOZ-FXQIFTODSA-N 0.000 description 1
- ZPDVKYLJTOFQJV-WDSKDSINSA-N Gln-Asn-Gly Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(O)=O ZPDVKYLJTOFQJV-WDSKDSINSA-N 0.000 description 1
- KYFSMWLWHYZRNW-ACZMJKKPSA-N Gln-Asp-Cys Chemical compound C(CC(=O)N)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CS)C(=O)O)N KYFSMWLWHYZRNW-ACZMJKKPSA-N 0.000 description 1
- MFLMFRZBAJSGHK-ACZMJKKPSA-N Gln-Cys-Ser Chemical compound C(CC(=O)N)[C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CO)C(=O)O)N MFLMFRZBAJSGHK-ACZMJKKPSA-N 0.000 description 1
- XFKUFUJECJUQTQ-CIUDSAMLSA-N Gln-Gln-Glu Chemical compound NC(=O)CC[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O XFKUFUJECJUQTQ-CIUDSAMLSA-N 0.000 description 1
- KVXVVDFOZNYYKZ-DCAQKATOSA-N Gln-Gln-Leu Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(O)=O KVXVVDFOZNYYKZ-DCAQKATOSA-N 0.000 description 1
- NPTGGVQJYRSMCM-GLLZPBPUSA-N Gln-Gln-Thr Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O NPTGGVQJYRSMCM-GLLZPBPUSA-N 0.000 description 1
- IKFZXRLDMYWNBU-YUMQZZPRSA-N Gln-Gly-Arg Chemical compound NC(=O)CC[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CCCN=C(N)N IKFZXRLDMYWNBU-YUMQZZPRSA-N 0.000 description 1
- TWTWUBHEWQPMQW-ZPFDUUQYSA-N Gln-Ile-Arg Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O TWTWUBHEWQPMQW-ZPFDUUQYSA-N 0.000 description 1
- XFAUJGNLHIGXET-AVGNSLFASA-N Gln-Leu-Leu Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O XFAUJGNLHIGXET-AVGNSLFASA-N 0.000 description 1
- YPMDZWPZFOZYFG-GUBZILKMSA-N Gln-Leu-Ser Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O YPMDZWPZFOZYFG-GUBZILKMSA-N 0.000 description 1
- MLSKFHLRFVGNLL-WDCWCFNPSA-N Gln-Leu-Thr Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O MLSKFHLRFVGNLL-WDCWCFNPSA-N 0.000 description 1
- HSHCEAUPUPJPTE-JYJNAYRXSA-N Gln-Leu-Tyr Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)O)NC(=O)[C@H](CCC(=O)N)N HSHCEAUPUPJPTE-JYJNAYRXSA-N 0.000 description 1
- UWKPRVKWEKEMSY-DCAQKATOSA-N Gln-Lys-Gln Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(N)=O)C(O)=O UWKPRVKWEKEMSY-DCAQKATOSA-N 0.000 description 1
- KLKYKPXITJBSNI-CIUDSAMLSA-N Gln-Met-Ala Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](C)C(O)=O KLKYKPXITJBSNI-CIUDSAMLSA-N 0.000 description 1
- LHMWTCWZARHLPV-CIUDSAMLSA-N Gln-Met-Ser Chemical compound CSCC[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CCC(=O)N)N LHMWTCWZARHLPV-CIUDSAMLSA-N 0.000 description 1
- JILRMFFFCHUUTJ-ACZMJKKPSA-N Gln-Ser-Ser Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O JILRMFFFCHUUTJ-ACZMJKKPSA-N 0.000 description 1
- STHSGOZLFLFGSS-SUSMZKCASA-N Gln-Thr-Thr Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O STHSGOZLFLFGSS-SUSMZKCASA-N 0.000 description 1
- IIMZHVKZBGSEKZ-SZMVWBNQSA-N Gln-Trp-Leu Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CC(C)C)C(O)=O IIMZHVKZBGSEKZ-SZMVWBNQSA-N 0.000 description 1
- GTBXHETZPUURJE-KKUMJFAQSA-N Gln-Tyr-Arg Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O GTBXHETZPUURJE-KKUMJFAQSA-N 0.000 description 1
- FITIQFSXXBKFFM-NRPADANISA-N Gln-Val-Ser Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(O)=O FITIQFSXXBKFFM-NRPADANISA-N 0.000 description 1
- WOMUDRVDJMHTCV-DCAQKATOSA-N Glu-Arg-Arg Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O WOMUDRVDJMHTCV-DCAQKATOSA-N 0.000 description 1
- ZJICFHQSPWFBKP-AVGNSLFASA-N Glu-Asn-Tyr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O ZJICFHQSPWFBKP-AVGNSLFASA-N 0.000 description 1
- HTTSBEBKVNEDFE-AUTRQRHGSA-N Glu-Gln-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CCC(=O)O)N HTTSBEBKVNEDFE-AUTRQRHGSA-N 0.000 description 1
- ZGKXAUIVGIBISK-SZMVWBNQSA-N Glu-His-Trp Chemical compound N[C@@H](CCC(O)=O)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(O)=O ZGKXAUIVGIBISK-SZMVWBNQSA-N 0.000 description 1
- ITBHUUMCJJQUSC-LAEOZQHASA-N Glu-Ile-Gly Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(O)=O ITBHUUMCJJQUSC-LAEOZQHASA-N 0.000 description 1
- ZHNHJYYFCGUZNQ-KBIXCLLPSA-N Glu-Ile-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H](N)CCC(O)=O ZHNHJYYFCGUZNQ-KBIXCLLPSA-N 0.000 description 1
- HVYWQYLBVXMXSV-GUBZILKMSA-N Glu-Leu-Ala Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(O)=O HVYWQYLBVXMXSV-GUBZILKMSA-N 0.000 description 1
- SJJHXJDSNQJMMW-SRVKXCTJSA-N Glu-Lys-Arg Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O SJJHXJDSNQJMMW-SRVKXCTJSA-N 0.000 description 1
- JHSRJMUJOGLIHK-GUBZILKMSA-N Glu-Met-Glu Chemical compound CSCC[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)O)NC(=O)[C@H](CCC(=O)O)N JHSRJMUJOGLIHK-GUBZILKMSA-N 0.000 description 1
- IDEODOAVGCMUQV-GUBZILKMSA-N Glu-Ser-Leu Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O IDEODOAVGCMUQV-GUBZILKMSA-N 0.000 description 1
- SOYWRINXUSUWEQ-DLOVCJGASA-N Glu-Val-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CCC(O)=O SOYWRINXUSUWEQ-DLOVCJGASA-N 0.000 description 1
- LJPIRKICOISLKN-WHFBIAKZSA-N Gly-Ala-Ser Chemical compound NCC(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(O)=O LJPIRKICOISLKN-WHFBIAKZSA-N 0.000 description 1
- XZRZILPOZBVTDB-GJZGRUSLSA-N Gly-Arg-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](CCCNC(N)=N)NC(=O)CN)C(O)=O)=CNC2=C1 XZRZILPOZBVTDB-GJZGRUSLSA-N 0.000 description 1
- NZAFOTBEULLEQB-WDSKDSINSA-N Gly-Asn-Glu Chemical compound C(CC(=O)O)[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)CN NZAFOTBEULLEQB-WDSKDSINSA-N 0.000 description 1
- GGEJHJIXRBTJPD-BYPYZUCNSA-N Gly-Asn-Gly Chemical compound NCC(=O)N[C@@H](CC(N)=O)C(=O)NCC(O)=O GGEJHJIXRBTJPD-BYPYZUCNSA-N 0.000 description 1
- BULIVUZUDBHKKZ-WDSKDSINSA-N Gly-Gln-Asn Chemical compound NCC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O BULIVUZUDBHKKZ-WDSKDSINSA-N 0.000 description 1
- AQLHORCVPGXDJW-IUCAKERBSA-N Gly-Gln-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)CN AQLHORCVPGXDJW-IUCAKERBSA-N 0.000 description 1
- ITZOBNKQDZEOCE-NHCYSSNCSA-N Gly-Ile-Lys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)CN ITZOBNKQDZEOCE-NHCYSSNCSA-N 0.000 description 1
- SCWYHUQOOFRVHP-MBLNEYKQSA-N Gly-Ile-Thr Chemical compound NCC(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(O)=O SCWYHUQOOFRVHP-MBLNEYKQSA-N 0.000 description 1
- NNCSJUBVFBDDLC-YUMQZZPRSA-N Gly-Leu-Ser Chemical compound NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O NNCSJUBVFBDDLC-YUMQZZPRSA-N 0.000 description 1
- FJWSJWACLMTDMI-WPRPVWTQSA-N Gly-Met-Val Chemical compound [H]NCC(=O)N[C@@H](CCSC)C(=O)N[C@@H](C(C)C)C(O)=O FJWSJWACLMTDMI-WPRPVWTQSA-N 0.000 description 1
- JJGBXTYGTKWGAT-YUMQZZPRSA-N Gly-Pro-Glu Chemical compound NCC(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(O)=O JJGBXTYGTKWGAT-YUMQZZPRSA-N 0.000 description 1
- FFJQHWKSGAWSTJ-BFHQHQDPSA-N Gly-Thr-Ala Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(O)=O FFJQHWKSGAWSTJ-BFHQHQDPSA-N 0.000 description 1
- JQFILXICXLDTRR-FBCQKBJTSA-N Gly-Thr-Gly Chemical compound NCC(=O)N[C@@H]([C@H](O)C)C(=O)NCC(O)=O JQFILXICXLDTRR-FBCQKBJTSA-N 0.000 description 1
- RHRLHXQWHCNJKR-PMVVWTBXSA-N Gly-Thr-His Chemical compound NCC(=O)N[C@@H]([C@H](O)C)C(=O)N[C@H](C(O)=O)CC1=CN=CN1 RHRLHXQWHCNJKR-PMVVWTBXSA-N 0.000 description 1
- FFALDIDGPLUDKV-ZDLURKLDSA-N Gly-Thr-Ser Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(O)=O FFALDIDGPLUDKV-ZDLURKLDSA-N 0.000 description 1
- UMBDRSMLCUYIRI-DVJZZOLTSA-N Gly-Trp-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)NC(=O)CN)O UMBDRSMLCUYIRI-DVJZZOLTSA-N 0.000 description 1
- NGRPGJGKJMUGDM-XVKPBYJWSA-N Gly-Val-Gln Chemical compound NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O NGRPGJGKJMUGDM-XVKPBYJWSA-N 0.000 description 1
- JBCLFWXMTIKCCB-UHFFFAOYSA-N H-Gly-Phe-OH Natural products NCC(=O)NC(C(O)=O)CC1=CC=CC=C1 JBCLFWXMTIKCCB-UHFFFAOYSA-N 0.000 description 1
- RVKIPWVMZANZLI-UHFFFAOYSA-N H-Lys-Trp-OH Natural products C1=CC=C2C(CC(NC(=O)C(N)CCCCN)C(O)=O)=CNC2=C1 RVKIPWVMZANZLI-UHFFFAOYSA-N 0.000 description 1
- HTZKFIYQMHJWSQ-INTQDDNPSA-N His-Ala-Pro Chemical compound C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CC2=CN=CN2)N HTZKFIYQMHJWSQ-INTQDDNPSA-N 0.000 description 1
- TVQGUFGDVODUIF-LSJOCFKGSA-N His-Arg-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC1=CN=CN1)N TVQGUFGDVODUIF-LSJOCFKGSA-N 0.000 description 1
- TTZAWSKKNCEINZ-AVGNSLFASA-N His-Arg-Val Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(O)=O TTZAWSKKNCEINZ-AVGNSLFASA-N 0.000 description 1
- DFHVLUKTTVTCKY-PBCZWWQYSA-N His-Asn-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CC1=CN=CN1)N)O DFHVLUKTTVTCKY-PBCZWWQYSA-N 0.000 description 1
- VLPMGIJPAWENQB-SRVKXCTJSA-N His-Cys-Leu Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(C)C)C(O)=O VLPMGIJPAWENQB-SRVKXCTJSA-N 0.000 description 1
- ZNNNYCXPCKACHX-DCAQKATOSA-N His-Gln-Gln Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O ZNNNYCXPCKACHX-DCAQKATOSA-N 0.000 description 1
- HIAHVKLTHNOENC-HGNGGELXSA-N His-Glu-Ala Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(O)=O HIAHVKLTHNOENC-HGNGGELXSA-N 0.000 description 1
- VTMLJMNQHKBPON-QWRGUYRKSA-N His-Gly-His Chemical compound C([C@H](N)C(=O)NCC(=O)N[C@@H](CC=1NC=NC=1)C(O)=O)C1=CN=CN1 VTMLJMNQHKBPON-QWRGUYRKSA-N 0.000 description 1
- LNVILFYCPVOHPV-IHPCNDPISA-N His-Trp-Leu Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CC(C)C)C(O)=O LNVILFYCPVOHPV-IHPCNDPISA-N 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101100108860 Homo sapiens ANGPT4 gene Proteins 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- KUHFPGIVBOCRMV-MNXVOIDGSA-N Ile-Gln-Leu Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CC(C)C)C(=O)O)N KUHFPGIVBOCRMV-MNXVOIDGSA-N 0.000 description 1
- JDAWAWXGAUZPNJ-ZPFDUUQYSA-N Ile-Glu-Arg Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N JDAWAWXGAUZPNJ-ZPFDUUQYSA-N 0.000 description 1
- LGMUPVWZEYYUMU-YVNDNENWSA-N Ile-Glu-Gln Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N LGMUPVWZEYYUMU-YVNDNENWSA-N 0.000 description 1
- PMMMQRVUMVURGJ-XUXIUFHCSA-N Ile-Leu-Pro Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N1CCC[C@H]1C(O)=O PMMMQRVUMVURGJ-XUXIUFHCSA-N 0.000 description 1
- NXRNRBOKDBIVKQ-CXTHYWKRSA-N Ile-Tyr-Tyr Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CC2=CC=C(C=C2)O)C(=O)O)N NXRNRBOKDBIVKQ-CXTHYWKRSA-N 0.000 description 1
- BQSLGJHIAGOZCD-CIUDSAMLSA-N Leu-Ala-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(O)=O BQSLGJHIAGOZCD-CIUDSAMLSA-N 0.000 description 1
- KSZCCRIGNVSHFH-UWVGGRQHSA-N Leu-Arg-Gly Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O KSZCCRIGNVSHFH-UWVGGRQHSA-N 0.000 description 1
- RFUBXQQFJFGJFV-GUBZILKMSA-N Leu-Asn-Gln Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O RFUBXQQFJFGJFV-GUBZILKMSA-N 0.000 description 1
- OIARJGNVARWKFP-YUMQZZPRSA-N Leu-Asn-Gly Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(O)=O OIARJGNVARWKFP-YUMQZZPRSA-N 0.000 description 1
- TWQIYNGNYNJUFM-NHCYSSNCSA-N Leu-Asn-Val Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(O)=O TWQIYNGNYNJUFM-NHCYSSNCSA-N 0.000 description 1
- PVMPDMIKUVNOBD-CIUDSAMLSA-N Leu-Asp-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O PVMPDMIKUVNOBD-CIUDSAMLSA-N 0.000 description 1
- VQPPIMUZCZCOIL-GUBZILKMSA-N Leu-Gln-Ala Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C(O)=O VQPPIMUZCZCOIL-GUBZILKMSA-N 0.000 description 1
- KAFOIVJDVSZUMD-UHFFFAOYSA-N Leu-Gln-Gln Natural products CC(C)CC(N)C(=O)NC(CCC(N)=O)C(=O)NC(CCC(N)=O)C(O)=O KAFOIVJDVSZUMD-UHFFFAOYSA-N 0.000 description 1
- GPICTNQYKHHHTH-GUBZILKMSA-N Leu-Gln-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(O)=O GPICTNQYKHHHTH-GUBZILKMSA-N 0.000 description 1
- HFBCHNRFRYLZNV-GUBZILKMSA-N Leu-Glu-Asp Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O HFBCHNRFRYLZNV-GUBZILKMSA-N 0.000 description 1
- QVFGXCVIXXBFHO-AVGNSLFASA-N Leu-Glu-Leu Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(O)=O QVFGXCVIXXBFHO-AVGNSLFASA-N 0.000 description 1
- ZFNLIDNJUWNIJL-WDCWCFNPSA-N Leu-Glu-Thr Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O ZFNLIDNJUWNIJL-WDCWCFNPSA-N 0.000 description 1
- FMEICTQWUKNAGC-YUMQZZPRSA-N Leu-Gly-Asn Chemical compound [H]N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(O)=O FMEICTQWUKNAGC-YUMQZZPRSA-N 0.000 description 1
- CSFVADKICPDRRF-KKUMJFAQSA-N Leu-His-Leu Chemical compound CC(C)C[C@H]([NH3+])C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C([O-])=O)CC1=CN=CN1 CSFVADKICPDRRF-KKUMJFAQSA-N 0.000 description 1
- HRTRLSRYZZKPCO-BJDJZHNGSA-N Leu-Ile-Ser Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(O)=O HRTRLSRYZZKPCO-BJDJZHNGSA-N 0.000 description 1
- LIINDKYIGYTDLG-PPCPHDFISA-N Leu-Ile-Thr Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(O)=O LIINDKYIGYTDLG-PPCPHDFISA-N 0.000 description 1
- IAJFFZORSWOZPQ-SRVKXCTJSA-N Leu-Leu-Asn Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O IAJFFZORSWOZPQ-SRVKXCTJSA-N 0.000 description 1
- JNDYEOUZBLOVOF-AVGNSLFASA-N Leu-Leu-Gln Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O JNDYEOUZBLOVOF-AVGNSLFASA-N 0.000 description 1
- YOKVEHGYYQEQOP-QWRGUYRKSA-N Leu-Leu-Gly Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O YOKVEHGYYQEQOP-QWRGUYRKSA-N 0.000 description 1
- RZXLZBIUTDQHJQ-SRVKXCTJSA-N Leu-Lys-Asp Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(O)=O RZXLZBIUTDQHJQ-SRVKXCTJSA-N 0.000 description 1
- IBSGMIPRBMPMHE-IHRRRGAJSA-N Leu-Met-Lys Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCCN)C(O)=O IBSGMIPRBMPMHE-IHRRRGAJSA-N 0.000 description 1
- FZMNAYBEFGZEIF-AVGNSLFASA-N Leu-Met-Met Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCSC)C(=O)O)N FZMNAYBEFGZEIF-AVGNSLFASA-N 0.000 description 1
- YRRCOJOXAJNSAX-IHRRRGAJSA-N Leu-Pro-Lys Chemical compound CC(C)C[C@@H](C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(=O)O)N YRRCOJOXAJNSAX-IHRRRGAJSA-N 0.000 description 1
- AKVBOOKXVAMKSS-GUBZILKMSA-N Leu-Ser-Gln Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(O)=O AKVBOOKXVAMKSS-GUBZILKMSA-N 0.000 description 1
- AEDWWMMHUGYIFD-HJGDQZAQSA-N Leu-Thr-Asn Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(O)=O AEDWWMMHUGYIFD-HJGDQZAQSA-N 0.000 description 1
- YQFZRHYZLARWDY-IHRRRGAJSA-N Leu-Val-Lys Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CCCCN YQFZRHYZLARWDY-IHRRRGAJSA-N 0.000 description 1
- DGWXCIORNLWGGG-CIUDSAMLSA-N Lys-Asn-Ser Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(O)=O DGWXCIORNLWGGG-CIUDSAMLSA-N 0.000 description 1
- NTBFKPBULZGXQL-KKUMJFAQSA-N Lys-Asp-Tyr Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 NTBFKPBULZGXQL-KKUMJFAQSA-N 0.000 description 1
- ZAWOJFFMBANLGE-CIUDSAMLSA-N Lys-Cys-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CS)NC(=O)[C@H](CCCCN)N ZAWOJFFMBANLGE-CIUDSAMLSA-N 0.000 description 1
- ZASPELYMPSACER-HOCLYGCPSA-N Lys-Gly-Trp Chemical compound [H]N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O ZASPELYMPSACER-HOCLYGCPSA-N 0.000 description 1
- OVAOHZIOUBEQCJ-IHRRRGAJSA-N Lys-Leu-Arg Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O OVAOHZIOUBEQCJ-IHRRRGAJSA-N 0.000 description 1
- NJNRBRKHOWSGMN-SRVKXCTJSA-N Lys-Leu-Asn Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O NJNRBRKHOWSGMN-SRVKXCTJSA-N 0.000 description 1
- ONPDTSFZAIWMDI-AVGNSLFASA-N Lys-Leu-Gln Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O ONPDTSFZAIWMDI-AVGNSLFASA-N 0.000 description 1
- SKRGVGLIRUGANF-AVGNSLFASA-N Lys-Leu-Glu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O SKRGVGLIRUGANF-AVGNSLFASA-N 0.000 description 1
- VMTYLUGCXIEDMV-QWRGUYRKSA-N Lys-Leu-Gly Chemical compound OC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCCCN VMTYLUGCXIEDMV-QWRGUYRKSA-N 0.000 description 1
- YPLVCBKEPJPBDQ-MELADBBJSA-N Lys-Leu-Pro Chemical compound CC(C)C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCCCN)N YPLVCBKEPJPBDQ-MELADBBJSA-N 0.000 description 1
- OIQSIMFSVLLWBX-VOAKCMCISA-N Lys-Leu-Thr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O OIQSIMFSVLLWBX-VOAKCMCISA-N 0.000 description 1
- SBQDRNOLGSYHQA-YUMQZZPRSA-N Lys-Ser-Gly Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)NCC(O)=O SBQDRNOLGSYHQA-YUMQZZPRSA-N 0.000 description 1
- VWJFOUBDZIUXGA-AVGNSLFASA-N Lys-Val-Met Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCSC)C(=O)O)NC(=O)[C@H](CCCCN)N VWJFOUBDZIUXGA-AVGNSLFASA-N 0.000 description 1
- GAELMDJMQDUDLJ-BQBZGAKWSA-N Met-Ala-Gly Chemical compound CSCC[C@H](N)C(=O)N[C@@H](C)C(=O)NCC(O)=O GAELMDJMQDUDLJ-BQBZGAKWSA-N 0.000 description 1
- CTVJSFRHUOSCQQ-DCAQKATOSA-N Met-Arg-Glu Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(O)=O CTVJSFRHUOSCQQ-DCAQKATOSA-N 0.000 description 1
- BQHLZUMZOXUWNU-DCAQKATOSA-N Met-Pro-Glu Chemical compound CSCC[C@@H](C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(=O)O)C(=O)O)N BQHLZUMZOXUWNU-DCAQKATOSA-N 0.000 description 1
- PCTFVQATEGYHJU-FXQIFTODSA-N Met-Ser-Asn Chemical compound [H]N[C@@H](CCSC)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(O)=O PCTFVQATEGYHJU-FXQIFTODSA-N 0.000 description 1
- FXBKQTOGURNXSL-HJGDQZAQSA-N Met-Thr-Glu Chemical compound CSCC[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@H](C(O)=O)CCC(O)=O FXBKQTOGURNXSL-HJGDQZAQSA-N 0.000 description 1
- SITLTJHOQZFJGG-UHFFFAOYSA-N N-L-alpha-glutamyl-L-valine Natural products CC(C)C(C(O)=O)NC(=O)C(N)CCC(O)=O SITLTJHOQZFJGG-UHFFFAOYSA-N 0.000 description 1
- KZNQNBZMBZJQJO-UHFFFAOYSA-N N-glycyl-L-proline Natural products NCC(=O)N1CCCC1C(O)=O KZNQNBZMBZJQJO-UHFFFAOYSA-N 0.000 description 1
- 108010002311 N-glycylglutamic acid Proteins 0.000 description 1
- 108010087066 N2-tryptophyllysine Proteins 0.000 description 1
- 102000007560 NF-E2-Related Factor 1 Human genes 0.000 description 1
- 108010071380 NF-E2-Related Factor 1 Proteins 0.000 description 1
- 101150060098 NFYA gene Proteins 0.000 description 1
- CGOMLCQJEMWMCE-STQMWFEESA-N Phe-Arg-Gly Chemical compound NC(N)=NCCC[C@@H](C(=O)NCC(O)=O)NC(=O)[C@@H](N)CC1=CC=CC=C1 CGOMLCQJEMWMCE-STQMWFEESA-N 0.000 description 1
- VADLTGVIOIOKGM-BZSNNMDCSA-N Phe-His-Leu Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)[C@@H](N)CC=1C=CC=CC=1)C1=CN=CN1 VADLTGVIOIOKGM-BZSNNMDCSA-N 0.000 description 1
- AUJWXNGCAQWLEI-KBPBESRZSA-N Phe-Lys-Gly Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCCCN)C(=O)NCC(O)=O AUJWXNGCAQWLEI-KBPBESRZSA-N 0.000 description 1
- 244000203593 Piper nigrum Species 0.000 description 1
- KIZQGKLMXKGDIV-BQBZGAKWSA-N Pro-Ala-Gly Chemical compound OC(=O)CNC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1 KIZQGKLMXKGDIV-BQBZGAKWSA-N 0.000 description 1
- QSKCKTUQPICLSO-AVGNSLFASA-N Pro-Arg-Lys Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCCCN)C(=O)O QSKCKTUQPICLSO-AVGNSLFASA-N 0.000 description 1
- OBVCYFIHIIYIQF-CIUDSAMLSA-N Pro-Asn-Glu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O OBVCYFIHIIYIQF-CIUDSAMLSA-N 0.000 description 1
- CLJLVCYFABNTHP-DCAQKATOSA-N Pro-Leu-Asp Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O CLJLVCYFABNTHP-DCAQKATOSA-N 0.000 description 1
- KDBHVPXBQADZKY-GUBZILKMSA-N Pro-Pro-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1 KDBHVPXBQADZKY-GUBZILKMSA-N 0.000 description 1
- BGWKULMLUIUPKY-BQBZGAKWSA-N Pro-Ser-Gly Chemical compound OC(=O)CNC(=O)[C@H](CO)NC(=O)[C@@H]1CCCN1 BGWKULMLUIUPKY-BQBZGAKWSA-N 0.000 description 1
- UGDMQJSXSSZUKL-IHRRRGAJSA-N Pro-Ser-Tyr Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC2=CC=C(C=C2)O)C(=O)O UGDMQJSXSSZUKL-IHRRRGAJSA-N 0.000 description 1
- QUBVFEANYYWBTM-VEVYYDQMSA-N Pro-Thr-Asp Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(O)=O QUBVFEANYYWBTM-VEVYYDQMSA-N 0.000 description 1
- AJJDPGVVNPUZCR-RHYQMDGZSA-N Pro-Thr-Lys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@@H]1CCCN1)O AJJDPGVVNPUZCR-RHYQMDGZSA-N 0.000 description 1
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 1
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 1
- ZUGXSSFMTXKHJS-ZLUOBGJFSA-N Ser-Ala-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(O)=O ZUGXSSFMTXKHJS-ZLUOBGJFSA-N 0.000 description 1
- BRKHVZNDAOMAHX-BIIVOSGPSA-N Ser-Ala-Pro Chemical compound C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CO)N BRKHVZNDAOMAHX-BIIVOSGPSA-N 0.000 description 1
- QWZIOCFPXMAXET-CIUDSAMLSA-N Ser-Arg-Gln Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(O)=O QWZIOCFPXMAXET-CIUDSAMLSA-N 0.000 description 1
- QFBNNYNWKYKVJO-DCAQKATOSA-N Ser-Arg-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CO)CCCN=C(N)N QFBNNYNWKYKVJO-DCAQKATOSA-N 0.000 description 1
- RZUOXAKGNHXZTB-GUBZILKMSA-N Ser-Arg-Met Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCSC)C(O)=O RZUOXAKGNHXZTB-GUBZILKMSA-N 0.000 description 1
- OOKCGAYXSNJBGQ-ZLUOBGJFSA-N Ser-Asn-Asn Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O OOKCGAYXSNJBGQ-ZLUOBGJFSA-N 0.000 description 1
- UGJRQLURDVGULT-LKXGYXEUSA-N Ser-Asn-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O UGJRQLURDVGULT-LKXGYXEUSA-N 0.000 description 1
- TUYBIWUZWJUZDD-ACZMJKKPSA-N Ser-Cys-Gln Chemical compound OC[C@H](N)C(=O)N[C@@H](CS)C(=O)N[C@H](C(O)=O)CCC(N)=O TUYBIWUZWJUZDD-ACZMJKKPSA-N 0.000 description 1
- IXUGADGDCQDLSA-FXQIFTODSA-N Ser-Gln-Gln Chemical compound C(CC(=O)N)[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CO)N IXUGADGDCQDLSA-FXQIFTODSA-N 0.000 description 1
- XWCYBVBLJRWOFR-WDSKDSINSA-N Ser-Gln-Gly Chemical compound OC[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(O)=O XWCYBVBLJRWOFR-WDSKDSINSA-N 0.000 description 1
- SQBLRDDJTUJDMV-ACZMJKKPSA-N Ser-Glu-Asn Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O SQBLRDDJTUJDMV-ACZMJKKPSA-N 0.000 description 1
- QKQDTEYDEIJPNK-GUBZILKMSA-N Ser-Glu-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CO QKQDTEYDEIJPNK-GUBZILKMSA-N 0.000 description 1
- UFKPDBLKLOBMRH-XHNCKOQMSA-N Ser-Glu-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CO)N)C(=O)O UFKPDBLKLOBMRH-XHNCKOQMSA-N 0.000 description 1
- BRIZMMZEYSAKJX-QEJZJMRPSA-N Ser-Glu-Trp Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CO)N BRIZMMZEYSAKJX-QEJZJMRPSA-N 0.000 description 1
- BPMRXBZYPGYPJN-WHFBIAKZSA-N Ser-Gly-Asn Chemical compound [H]N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(O)=O BPMRXBZYPGYPJN-WHFBIAKZSA-N 0.000 description 1
- YMTLKLXDFCSCNX-BYPYZUCNSA-N Ser-Gly-Gly Chemical compound OC[C@H](N)C(=O)NCC(=O)NCC(O)=O YMTLKLXDFCSCNX-BYPYZUCNSA-N 0.000 description 1
- XXXAXOWMBOKTRN-XPUUQOCRSA-N Ser-Gly-Val Chemical compound [H]N[C@@H](CO)C(=O)NCC(=O)N[C@@H](C(C)C)C(O)=O XXXAXOWMBOKTRN-XPUUQOCRSA-N 0.000 description 1
- CAOYHZOWXFFAIR-CIUDSAMLSA-N Ser-His-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CO)C(O)=O CAOYHZOWXFFAIR-CIUDSAMLSA-N 0.000 description 1
- RIAKPZVSNBBNRE-BJDJZHNGSA-N Ser-Ile-Leu Chemical compound OC[C@H](N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(O)=O RIAKPZVSNBBNRE-BJDJZHNGSA-N 0.000 description 1
- QYSFWUIXDFJUDW-DCAQKATOSA-N Ser-Leu-Arg Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O QYSFWUIXDFJUDW-DCAQKATOSA-N 0.000 description 1
- YUJLIIRMIAGMCQ-CIUDSAMLSA-N Ser-Leu-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O YUJLIIRMIAGMCQ-CIUDSAMLSA-N 0.000 description 1
- CRJZZXMAADSBBQ-SRVKXCTJSA-N Ser-Lys-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CO CRJZZXMAADSBBQ-SRVKXCTJSA-N 0.000 description 1
- PMCMLDNPAZUYGI-DCAQKATOSA-N Ser-Lys-Val Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(O)=O PMCMLDNPAZUYGI-DCAQKATOSA-N 0.000 description 1
- BMKNXTJLHFIAAH-CIUDSAMLSA-N Ser-Ser-Leu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O BMKNXTJLHFIAAH-CIUDSAMLSA-N 0.000 description 1
- SQHKXWODKJDZRC-LKXGYXEUSA-N Ser-Thr-Asn Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(O)=O SQHKXWODKJDZRC-LKXGYXEUSA-N 0.000 description 1
- VVKVHAOOUGNDPJ-SRVKXCTJSA-N Ser-Tyr-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CO)C(O)=O VVKVHAOOUGNDPJ-SRVKXCTJSA-N 0.000 description 1
- PMTWIUBUQRGCSB-FXQIFTODSA-N Ser-Val-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C)C(O)=O PMTWIUBUQRGCSB-FXQIFTODSA-N 0.000 description 1
- LLSLRQOEAFCZLW-NRPADANISA-N Ser-Val-Gln Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O LLSLRQOEAFCZLW-NRPADANISA-N 0.000 description 1
- SYCFMSYTIFXWAJ-DCAQKATOSA-N Ser-Val-His Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](CO)N SYCFMSYTIFXWAJ-DCAQKATOSA-N 0.000 description 1
- FQPQPTHMHZKGFM-XQXXSGGOSA-N Thr-Ala-Glu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(O)=O FQPQPTHMHZKGFM-XQXXSGGOSA-N 0.000 description 1
- GFDUZZACIWNMPE-KZVJFYERSA-N Thr-Ala-Met Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCSC)C(O)=O GFDUZZACIWNMPE-KZVJFYERSA-N 0.000 description 1
- SKHPKKYKDYULDH-HJGDQZAQSA-N Thr-Asn-Leu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(O)=O SKHPKKYKDYULDH-HJGDQZAQSA-N 0.000 description 1
- JTEICXDKGWKRRV-HJGDQZAQSA-N Thr-Asn-Lys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CCCCN)C(=O)O)N)O JTEICXDKGWKRRV-HJGDQZAQSA-N 0.000 description 1
- ZQUKYJOKQBRBCS-GLLZPBPUSA-N Thr-Gln-Gln Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N)O ZQUKYJOKQBRBCS-GLLZPBPUSA-N 0.000 description 1
- XPNSAQMEAVSQRD-FBCQKBJTSA-N Thr-Gly-Gly Chemical compound C[C@@H](O)[C@H](N)C(=O)NCC(=O)NCC(O)=O XPNSAQMEAVSQRD-FBCQKBJTSA-N 0.000 description 1
- UBDDORVPVLEECX-FJXKBIBVSA-N Thr-Gly-Met Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CCSC)C(O)=O UBDDORVPVLEECX-FJXKBIBVSA-N 0.000 description 1
- URPSJRMWHQTARR-MBLNEYKQSA-N Thr-Ile-Gly Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(O)=O URPSJRMWHQTARR-MBLNEYKQSA-N 0.000 description 1
- ADPHPKGWVDHWML-PPCPHDFISA-N Thr-Ile-Leu Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)O)NC(=O)[C@H]([C@@H](C)O)N ADPHPKGWVDHWML-PPCPHDFISA-N 0.000 description 1
- XNTVWRJTUIOGQO-RHYQMDGZSA-N Thr-Met-Leu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(C)C)C(O)=O XNTVWRJTUIOGQO-RHYQMDGZSA-N 0.000 description 1
- SGAOHNPSEPVAFP-ZDLURKLDSA-N Thr-Ser-Gly Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)NCC(O)=O SGAOHNPSEPVAFP-ZDLURKLDSA-N 0.000 description 1
- XZUBGOYOGDRYFC-XGEHTFHBSA-N Thr-Ser-Met Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCSC)C(O)=O XZUBGOYOGDRYFC-XGEHTFHBSA-N 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 102100026893 Troponin T, cardiac muscle Human genes 0.000 description 1
- 101710165323 Troponin T, cardiac muscle Proteins 0.000 description 1
- CZWIHKFGHICAJX-BPUTZDHNSA-N Trp-Glu-Glu Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O)=CNC2=C1 CZWIHKFGHICAJX-BPUTZDHNSA-N 0.000 description 1
- VMBBTANKMSRJSS-JSGCOSHPSA-N Trp-Glu-Gly Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(O)=O VMBBTANKMSRJSS-JSGCOSHPSA-N 0.000 description 1
- FHVCMIMUGUFIOJ-IHPCNDPISA-N Trp-His-His Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CC3=CN=CN3)C(=O)N[C@@H](CC4=CN=CN4)C(=O)O)N FHVCMIMUGUFIOJ-IHPCNDPISA-N 0.000 description 1
- OAZLRFLMQASGNW-PMVMPFDFSA-N Trp-His-Tyr Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CC3=CN=CN3)C(=O)N[C@@H](CC4=CC=C(C=C4)O)C(=O)O)N OAZLRFLMQASGNW-PMVMPFDFSA-N 0.000 description 1
- RRVUOLRWIZXBRQ-IHPCNDPISA-N Trp-Leu-Lys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)N RRVUOLRWIZXBRQ-IHPCNDPISA-N 0.000 description 1
- KRCPXGSWDOGHAM-XIRDDKMYSA-N Trp-Lys-Asp Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(O)=O KRCPXGSWDOGHAM-XIRDDKMYSA-N 0.000 description 1
- XKTWZYNTLXITCY-QRTARXTBSA-N Trp-Val-Asn Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O)=CNC2=C1 XKTWZYNTLXITCY-QRTARXTBSA-N 0.000 description 1
- XLMDWQNAOKLKCP-XDTLVQLUSA-N Tyr-Ala-Gln Chemical compound C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)N XLMDWQNAOKLKCP-XDTLVQLUSA-N 0.000 description 1
- LMLBOGIOLHZXOT-JYJNAYRXSA-N Tyr-Glu-His Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CC2=CN=CN2)C(=O)O)N)O LMLBOGIOLHZXOT-JYJNAYRXSA-N 0.000 description 1
- WPXKRJVHBXYLDT-JUKXBJQTSA-N Tyr-His-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CC1=CN=CN1)NC(=O)[C@H](CC2=CC=C(C=C2)O)N WPXKRJVHBXYLDT-JUKXBJQTSA-N 0.000 description 1
- GGXUDPQWAWRINY-XEGUGMAKSA-N Tyr-Ile-Gly Chemical compound OC(=O)CNC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 GGXUDPQWAWRINY-XEGUGMAKSA-N 0.000 description 1
- BYAKMYBZADCNMN-JYJNAYRXSA-N Tyr-Lys-Gln Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(N)=O)C(O)=O BYAKMYBZADCNMN-JYJNAYRXSA-N 0.000 description 1
- GZOCMHSZGGJBCX-ULQDDVLXSA-N Tyr-Lys-Met Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCSC)C(O)=O GZOCMHSZGGJBCX-ULQDDVLXSA-N 0.000 description 1
- ZPFLBLFITJCBTP-QWRGUYRKSA-N Tyr-Ser-Gly Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CO)C(=O)NCC(O)=O ZPFLBLFITJCBTP-QWRGUYRKSA-N 0.000 description 1
- MQGGXGKQSVEQHR-KKUMJFAQSA-N Tyr-Ser-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 MQGGXGKQSVEQHR-KKUMJFAQSA-N 0.000 description 1
- NZBSVMQZQMEUHI-WZLNRYEVSA-N Tyr-Thr-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)N NZBSVMQZQMEUHI-WZLNRYEVSA-N 0.000 description 1
- LDKDSFQSEUOCOO-RPTUDFQQSA-N Tyr-Thr-Phe Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O LDKDSFQSEUOCOO-RPTUDFQQSA-N 0.000 description 1
- HNWQUBBOBKSFQV-AVGNSLFASA-N Val-Arg-His Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N HNWQUBBOBKSFQV-AVGNSLFASA-N 0.000 description 1
- HURRXSNHCCSJHA-AUTRQRHGSA-N Val-Gln-Gln Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N HURRXSNHCCSJHA-AUTRQRHGSA-N 0.000 description 1
- XGJLNBNZNMVJRS-NRPADANISA-N Val-Glu-Ala Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(O)=O XGJLNBNZNMVJRS-NRPADANISA-N 0.000 description 1
- DLMNFMXSNGTSNJ-PYJNHQTQSA-N Val-His-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CC1=CN=CN1)NC(=O)[C@H](C(C)C)N DLMNFMXSNGTSNJ-PYJNHQTQSA-N 0.000 description 1
- HGJRMXOWUWVUOA-GVXVVHGQSA-N Val-Leu-Gln Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](C(C)C)N HGJRMXOWUWVUOA-GVXVVHGQSA-N 0.000 description 1
- LYERIXUFCYVFFX-GVXVVHGQSA-N Val-Leu-Glu Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)O)NC(=O)[C@H](C(C)C)N LYERIXUFCYVFFX-GVXVVHGQSA-N 0.000 description 1
- WBAJDGWKRIHOAC-GVXVVHGQSA-N Val-Lys-Gln Chemical compound [H]N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(N)=O)C(O)=O WBAJDGWKRIHOAC-GVXVVHGQSA-N 0.000 description 1
- UZFNHAXYMICTBU-DZKIICNBSA-N Val-Phe-Gln Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N UZFNHAXYMICTBU-DZKIICNBSA-N 0.000 description 1
- AJNUKMZFHXUBMK-GUBZILKMSA-N Val-Ser-Arg Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N AJNUKMZFHXUBMK-GUBZILKMSA-N 0.000 description 1
- OWFGFHQMSBTKLX-UFYCRDLUSA-N Val-Tyr-Tyr Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CC2=CC=C(C=C2)O)C(=O)O)N OWFGFHQMSBTKLX-UFYCRDLUSA-N 0.000 description 1
- VVIZITNVZUAEMI-DLOVCJGASA-N Val-Val-Gln Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CCC(N)=O VVIZITNVZUAEMI-DLOVCJGASA-N 0.000 description 1
- AEFJNECXZCODJM-UWVGGRQHSA-N Val-Val-Gly Chemical compound CC(C)[C@H]([NH3+])C(=O)N[C@@H](C(C)C)C(=O)NCC([O-])=O AEFJNECXZCODJM-UWVGGRQHSA-N 0.000 description 1
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 108010086434 alanyl-seryl-glycine Proteins 0.000 description 1
- 108010047495 alanylglycine Proteins 0.000 description 1
- KOSRFJWDECSPRO-UHFFFAOYSA-N alpha-L-glutamyl-L-glutamic acid Natural products OC(=O)CCC(N)C(=O)NC(CCC(O)=O)C(O)=O KOSRFJWDECSPRO-UHFFFAOYSA-N 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 108010013835 arginine glutamate Proteins 0.000 description 1
- 108010052670 arginyl-glutamyl-glutamic acid Proteins 0.000 description 1
- 108010091092 arginyl-glycyl-proline Proteins 0.000 description 1
- 108010068380 arginylarginine Proteins 0.000 description 1
- 108010069205 aspartyl-phenylalanine Proteins 0.000 description 1
- 108010092854 aspartyllysine Proteins 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 238000010009 beating Methods 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 108010016616 cysteinylglycine Proteins 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 230000013020 embryo development Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000013604 expression vector Substances 0.000 description 1
- 230000004720 fertilization Effects 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 108010078144 glutaminyl-glycine Proteins 0.000 description 1
- 108010037389 glutamyl-cysteinyl-lysine Proteins 0.000 description 1
- 108010055341 glutamyl-glutamic acid Proteins 0.000 description 1
- XBGGUPMXALFZOT-UHFFFAOYSA-N glycyl-L-tyrosine hemihydrate Natural products NCC(=O)NC(C(O)=O)CC1=CC=C(O)C=C1 XBGGUPMXALFZOT-UHFFFAOYSA-N 0.000 description 1
- 108010019832 glycyl-asparaginyl-glycine Proteins 0.000 description 1
- 108010062266 glycyl-glycyl-argininal Proteins 0.000 description 1
- 108010001064 glycyl-glycyl-glycyl-glycine Proteins 0.000 description 1
- 108010010147 glycylglutamine Proteins 0.000 description 1
- 108010050848 glycylleucine Proteins 0.000 description 1
- 108010081551 glycylphenylalanine Proteins 0.000 description 1
- 108010087823 glycyltyrosine Proteins 0.000 description 1
- 108010037850 glycylvaline Proteins 0.000 description 1
- 210000002064 heart cell Anatomy 0.000 description 1
- 210000005003 heart tissue Anatomy 0.000 description 1
- 108010036413 histidylglycine Proteins 0.000 description 1
- 108010025306 histidylleucine Proteins 0.000 description 1
- 108010092114 histidylphenylalanine Proteins 0.000 description 1
- 230000001146 hypoxic effect Effects 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 108010044374 isoleucyl-tyrosine Proteins 0.000 description 1
- 108010053037 kyotorphin Proteins 0.000 description 1
- 108010051673 leucyl-glycyl-phenylalanine Proteins 0.000 description 1
- 108010045397 lysyl-tyrosyl-lysine Proteins 0.000 description 1
- 108010054155 lysyllysine Proteins 0.000 description 1
- 108010017391 lysylvaline Proteins 0.000 description 1
- 108010063431 methionyl-aspartyl-glycine Proteins 0.000 description 1
- 108010056582 methionylglutamic acid Proteins 0.000 description 1
- 210000000663 muscle cell Anatomy 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 108010018625 phenylalanylarginine Proteins 0.000 description 1
- 108010012581 phenylalanylglutamate Proteins 0.000 description 1
- 239000013600 plasmid vector Substances 0.000 description 1
- 230000000270 postfertilization Effects 0.000 description 1
- 108010014614 prolyl-glycyl-proline Proteins 0.000 description 1
- 108010008359 protein kinase C lambda Proteins 0.000 description 1
- 230000010349 pulsation Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 108010048818 seryl-histidine Proteins 0.000 description 1
- 108010026333 seryl-proline Proteins 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 108010071097 threonyl-lysyl-proline Proteins 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 108010080629 tryptophan-leucine Proteins 0.000 description 1
- 108010051110 tyrosyl-lysine Proteins 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 241000701161 unidentified adenovirus Species 0.000 description 1
- 238000010200 validation analysis Methods 0.000 description 1
- 239000013603 viral vector Substances 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
Images
Classifications
-
- 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
- C07K14/515—Angiogenesic factors; Angiogenin
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; CARE OF BIRDS, FISHES, INSECTS; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K67/00—Rearing or breeding animals, not otherwise provided for; New breeds of animals
- A01K67/027—New breeds of vertebrates
- A01K67/0275—Genetically modified vertebrates, e.g. transgenic
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
-
- 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
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- 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
- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
- C12N5/06—Animal cells or tissues; Human cells or tissues
- C12N5/0602—Vertebrate cells
- C12N5/0652—Cells of skeletal and connective tissues; Mesenchyme
- C12N5/0657—Cardiomyocytes; Heart cells
-
- 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
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; CARE OF BIRDS, FISHES, INSECTS; 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; CARE OF BIRDS, FISHES, INSECTS; 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
- A01K2267/0375—Animal model for cardiovascular diseases
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/32—Cardiovascular disorders
Abstract
本发明涉及生物医药领域，具体涉及ANGPT4蛋白及其编码基因在调控心脏损伤后的修复与再生能力中的应用。本发明发现了ANGPT4蛋白及其编码基因对心脏损伤后的修复与再生能力的关键调控作用，且该作用在哺乳动物中高度保守，有助于推动相关治疗及诊断药物的研发与应用。同时，ANGPT4作为一种分泌蛋白和信号通路配体，为外源递送药物提供了极大便利。而且angpt4突变体不影响发育过程，表明以ANGPT4为靶标调控心脏再生的风险性更小。综上，本发明发现了一种风险性更小、更利于递送、利于时间控制与定量、哺乳动物保守的基因靶标，为治疗人类心血管疾病提供了新的思路。
Description
技术领域
本发明涉及生物医药领域，具体涉及ANGPT4蛋白及其编码基因在调控心脏损伤后的修复与再生能力中的应用。
背景技术
心肌梗塞是当今世界范围内致死率最高的疾病之一(Benjamin et al.,2019；Virani et al.,2020)。心肌梗塞主要由冠状动脉栓塞导致的心肌急性缺血引起，从而造成心肌细胞缺氧坏死或凋亡(Pfeffer and Braunwald,1990；Reeve et al.,2005)。在成年哺乳动物中，受损的心肌不能再生，而是被纤维化的瘢痕组织替代。瘢痕组织能够保持心室壁的完整性，但是大大降低了心脏的收缩能力，最终导致心衰(Frangogiannis,2006；Holmeset al.,2005；Jessup and Brozena,2003；Kehat and Molkentin,2010)。尽管心肌梗塞之后的早期介入治疗可以缓解患者的症状，但是现阶段心肌梗塞的治愈方法只有心脏的移植手术(Augoustides and Riha,2009)。因此，寻找促进心脏再生的方法有助于大大降低心肌梗塞的发病率和死亡率。
目前对促进心脏再生的探索仍然局限在基础研究中。小鼠在出生后一周内很快丧失了其心脏心脏再生的能力。有研究通过单细胞转录组测序探究出生后1天(P1，即具有再生能力)和出生后8天(P8，即不具有再生能力)的小鼠转录组水平的变化，发现与P8小鼠相比，P1小鼠损伤后特异性高表达一系列基因。进一步研究表明，过表达转录因子NFYa和NFE2L1可以促进小鼠心脏损伤后心肌细胞的增殖能力，提高小鼠心脏功能恢复(Cui etal.,2020)。
与哺乳动物不同的是，斑马鱼能够在心脏受损之后快速且有效地再生，而不留下永久的瘢痕组织(Poss et al.,2002)。并且，斑马鱼在心脏发育和功能上与哺乳动物高度相似，是一种很好的研究心脏再生的脊椎动物模型。有研究发现，心脏受损后Nrg1会迅速在心外膜细胞中表达，并且过表达Nrg1会促进斑马鱼心脏损伤后心肌细胞的增殖能力(Gemberling et al.,2015)。然而，在未损伤的斑马鱼中过表达Nrg1会使心肌细胞大量增殖，进而引起心室壁的增厚。同时，在小鼠中过表达NRG1可以促进心肌细胞增殖能力和损伤后的修复(Bersell et al.,2009)。但是，NRG1突变会导致小鼠在胚胎期死亡(Meyer andBirchmeier,1995)，表明这一基因在正常发育过程中也有功能。最近在斑马鱼中发现的另一心脏再生调控因子Klf1在心脏受损后特异性上调(Ogawa et al.,2021)。其突变不影响斑马鱼的正常发育，而阻遏斑马鱼的心脏再生。但其过表达会导致斑马鱼心脏在未损伤的情况下出现心衰症状。所以，调控Nrg1和Klf1等基因的表达需要在时间和细胞类型上精确控制，为药物转化增加了难度。
此外，目前以斑马鱼为模式动物发现的基因大多未在哺乳动物中验证，其保守性需要进一步地探究。能够促进哺乳动物心脏损伤后修复能力的基因，基本上都编码胞内蛋白。由于胞内蛋白难以递送至体内，尤其是递送至细胞内，且表达量难以控制，在转化为药物治疗方面存在很大的难度。此外，这些基因中的很大一部分都可能影响本身发育过程，药物转化安全性有待考量。
发明内容
本发明通过对斑马鱼心脏发育和再生过程进行单细胞测序，发现了心脏再生的关键调控因子ANGPT4(Angiopoietin 4，血管生成素4)。ANGPT4在心脏损伤后特异表达，并对心脏再生过程不可或缺。在进一步研究和验证后，本发明提供了ANGPT4蛋白及其编码基因在调控心脏损伤后的修复与再生能力中的应用。
具体而言，本发明首先提供ANGPT4蛋白、或其转录本、或其编码基因、或含有其编码基因的生物材料、或其关键结构域、或其表达促进剂、或其表达抑制剂、或其突变体、或其下游受体促进剂、或其下游受体抑制剂在以下至少一方面的应用：
a)在调控动物或人心脏损伤后的修复与再生能力中的应用；
b)在制备用于调控动物或人心脏损伤后的修复与再生能力的药物中的应用。
当个体表达或过表达ANGPT4蛋白、或促进下游受体时，其在心脏损伤后的修复与再生能力表现为更强；当个体的ANGPT4蛋白的表达受到抑制或抑制其下游受体时，其在心脏损伤后的修复与再生能力表现为更弱。
本发明中所提到的“在调控动物或人心脏损伤后的修复与再生能力中的应用”包括治疗目的的应用、诊断目的的应用以及非诊断治疗目的的应用。其中，治疗目的的应用包括：在预防、减缓、治疗与动物或人心脏损伤相关的疾病或使所述疾病消退中的应用，在减少动物或人心脏损伤后纤维化的瘢痕组织中的应用，等等；诊断目的的应用包括：在预测动物或人心脏损伤后的修复与再生能力中的应用、在检测动物或人心脏损伤情况中的应用，等等；非诊断治疗目的的应用包括：构建心脏再生缺陷动物模型，促进或抑制心肌细胞增殖，等等。
作为促进ANGPT4蛋白表达的一种实施方式，可以在所述心肌细胞中导入过表达ANGPT4基因的腺相关病毒9载体。在具体实施时，也可以在所述心肌细胞中导入表达或过表达ANGPT4基因的其他表达载体或使用表达促进剂的方式来促进ANGPT4蛋白的表达。
作为抑制ANGPT4蛋白表达的一种实施方式，可针对angpt4的第1个外显子设计gRNA，靶点序列为GGGAACGGTCAAGGGAGACGCGG(SEQ ID No.2，序列末尾的“CGG”为PAM区序列)，并筛选得到2-bp的缺失突变。突变位点之后的angpt4转录本发生移码突变，并且产生一个提前的终止密码子，进而导致形成一个仅有123个氨基酸残基的无功能的ANGPT4蛋白。在具体实施时，也可以构建大片段缺失突变或通过使用表达抑制剂的方式来抑制ANGPT4蛋白的表达。
另一方面，本发明还提供ANGPT4蛋白、或其转录本、或其编码基因、或含有其编码基因的生物材料、或其关键结构域、或其表达促进剂、或其下游受体促进剂在以下至少一方面的应用：
a)在预防、减缓、治疗与动物或人心脏损伤相关的疾病或使所述疾病消退中的应用；
b)在制备用于预防、减缓、治疗与动物或人心脏损伤相关的疾病或使所述疾病消退的药物中的应用。
优选地，所述疾病为心肌细胞损伤、坏死或凋亡所导致的疾病。
更优选地，所述疾病为缺血性心脏病(包括心肌梗塞)。
另一方面，本发明还提供ANGPT4蛋白、或其转录本、或其编码基因、或含有其编码基因的生物材料、或其关键结构域、或其表达促进剂、或其下游受体促进剂在以下至少一方面的应用：
a)在减少动物或人心脏损伤后纤维化的瘢痕组织中的应用；
b)在制备用于减少动物或人心脏损伤后纤维化的瘢痕组织的药物中的应用。
进一步的，本发明还发现，所述药物通过调控心肌细胞的增殖能力和/或激活内皮细胞中的Tie2-MAPK信号通路来实现对心脏损伤后的修复与再生能力的调控。
作为优选，所述下游受体为Tie2。
另一方面，根据本发明的发现，本领域人员可以将ANGPT4蛋白或其编码基因、或含有其编码基因的生物材料、或其关键结构域应用于预测动物或人心脏损伤后的修复与再生能力的试剂或试剂盒中的应用。
据此，本发明还提供ANGPT4蛋白或其编码基因、或含有其编码基因的生物材料、或其关键结构域在以下至少一方面的应用：
a)在预测动物或人心脏损伤后的修复与再生能力中的应用；
b)在制备用于预测动物或人心脏损伤后的修复与再生能力的试剂或试剂盒中的应用。
若个体可以表达或过表达ANGPT4蛋白时，可推定其在心脏损伤后的修复与再生能力表现为更强；若个体的ANGPT4蛋白的表达受到抑制时，可推定其在心脏损伤后的修复与再生能力表现为更弱。
另一方面，本发明还发现，根据个体体内ANGPT4蛋白的表达可以推测其心脏的受损情况，本领域人员可以在检测动物或人心脏损伤情况对ANGPT4蛋白或其编码基因、或含有其编码基因的生物材料进行应用。
据此，本发明还提供ANGPT4蛋白或其编码基因、或含有其编码基因的生物材料、或其关键结构域在以下至少一方面的应用：
a)在检测动物或人心脏损伤情况中的应用；
b)在制备用于检测动物或人心脏损伤情况的试剂或试剂盒中的应用。
若检测到个体的体内存在ANGPT4蛋白的明显表达(如表达量明显超出常规值)，可推定其心脏受到损伤；反之，可推定其心脏未受到损伤。
进一步的，本发明还发现，所述心脏损伤具体为心室损伤。
作为优选，所述动物为哺乳动物，比如可以为小鼠或人。
本发明发现，ANGPT4对心脏再生的调控作用在哺乳动物中高度保守。体外处理ANGPT4重组蛋白可以促进乳大鼠心肌细胞的增殖能力。体内过表达ANGPT4可以促进小鼠心肌梗塞后的心肌细胞增殖能力和功能恢复。
作为优选，所述ANGPT4蛋白或其编码基因源自灵长目、啮齿目、偶蹄目或鲤形目的物种；优选其源自人、猴、小鼠、大鼠、猪或斑马鱼。
进一步优选地，所述ANGPT4蛋白具有以下任意一种氨基酸序列：
1)SEQ ID NO.1或3所示的氨基酸序列；或
2)SEQ ID NO.1或3所示的氨基酸序列经过一个或多个氨基酸残基的替换、缺失或插入获得的具有相同功能蛋白的氨基酸序列。
上述所提到的优选方案也同样能在以下的方法和产品中进行应用。
本发明还提供一种非治疗目的的促进心肌细胞增殖的方法，其包括在心肌细胞内表达或过表达ANGPT4蛋白；
所述表达或过表达ANGPT4蛋白的方式包括：在所述心肌细胞中导入表达或过表达ANGPT4蛋白的载体，和/或，对心肌细胞施用ANGPT4蛋白的表达促进剂；然后对心肌细胞进行体外培养。
本发明还提供一种非治疗目的的抑制心肌细胞增殖的方法，其包括在心肌细胞内抑制或消除ANGPT4蛋白的表达；
所述抑制或消除ANGPT4蛋白的表达的方式包括：在所述心肌细胞中导入抑制或消除ANGPT4蛋白表达的载体，和/或，对心肌细胞施用ANGPT4蛋白的表达抑制剂；然后对心肌细胞进行体外培养。
本发明还提供一种心脏再生缺陷动物模型的构建方法，其包括在对象中抑制ANGPT4蛋白的编码基因的表达，所述抑制可以是心脏特异性的或全局性的。
本发明还提供一种生物材料，其含有ANGPT4蛋白的编码基因；所述生物材料选自表达盒、载体、宿主细胞和重组菌的一种或多种。
本发明还提供一种药物组合物，其含有：
ANGPT4蛋白、或其转录本、或其编码基因、或含有其编码基因的生物材料、或其关键结构域、或其表达促进剂、或其下游受体促进剂中的一种或多种；
以及，药学上可接受、且辅助其用于以下至少一种用途的辅料：1)预防、减缓、治疗与动物或人心脏损伤相关的疾病或使所述疾病消退；2)减少动物或人心脏损伤后纤维化的瘢痕组织。
在一种实施方式中，所述药物组合物含有基因治疗载体以及药学上可接受的辅料；所述基因治疗载体含有能够编码ANGPT4功能蛋白的基因序列和与其可操作性连接的表达调控序列；所述载体可以为质粒载体，病毒载体(如腺病毒载体)或者细菌载体等。
本发明还提供一种试剂盒，其含有用于检测ANGPT4蛋白或其编码基因、或含有其编码基因的生物材料、或其关键结构域中的一种或多种物质的试剂；以用于以下至少一种用途：1)预测动物或人心脏损伤后的修复与再生能力；2)检测动物或人心脏损伤情况。
本发明所提到的生物材料为表达盒、载体、宿主细胞或重组菌。
本领域人员可依照常规方法确定ANGPT4蛋白的关键结构域，如其C端纤维蛋白原结构域。
基于上述方案，本发明的有益效果如下：
本发明发现了ANGPT4蛋白及其编码基因对心脏损伤后的修复与再生能力的关键调控作用，且该作用在哺乳动物中高度保守，有助于推动相关治疗及诊断药物的研发与应用。同时，ANGPT4作为一种分泌蛋白和信号通路配体，为外源递送药物提供了极大便利。而且angpt4突变体不影响发育过程，且在心脏未损伤情况下过表达不会导致心衰症状，表明以ANGPT4为靶标调控心脏再生的风险性更小。综上，本发明发现了一种风险性更小、更利于递送、利于时间控制与定量、哺乳动物保守的基因靶标，为治疗人类心血管疾病提供了新的思路。
附图说明
图1：斑马鱼心脏发育和再生过程中的分子特征。其中，(A)图为所有细胞的t-SNE分群结果，不同形状代表不同细胞亚群。CM-A，心房心肌细胞；CM-V，心室心肌细胞；EC，心内皮细胞；EP，心外膜细胞；EPDC，心外膜衍生细胞。(B)图为经典心脏标记基因的表达量条形图。
图2：斑马鱼发育和再生过程中非心肌细胞的基因表达特征。其中，(A)图为非心肌细胞的t-SNE分群结果，不同形状代表不同的细胞亚群。PC，增殖祖细胞。(B)图为MTZ处理的细胞在各细胞群中的比例。
图3：angpt4突变体斑马鱼具有正常的胚胎发育和心脏形态。其中，(A)图为野生型斑马鱼与angpt4突变体受精后4天(4days post fertilization,dpf)时的胚胎形态。标尺：400μm。(B-C)图为野生型斑马鱼与angpt4突变体胚胎存活率(B)和产卵数(C)的统计分析。ns：p>0.05。(D)图为野生型斑马鱼与angpt4突变体成体心脏形态。标尺：200μm。(E-F)图为野生型斑马鱼与angpt4突变体心室最大截面积(E)和心脏重量与体重比值(F)的统计分析。ns：p>0.05。
图4：angpt4突变体胚胎心脏再生受阻。其中，(A)图具体为MTZ处理后4dpt野生型斑马鱼的心室和心房形态，(B)图具体为angpt4突变体4dpt的心室和心房形态。与野生型相比，angpt4突变体不能再生受损的心室，但心房依然具有正常的形态。
图5：angpt4突变体胚胎心脏损伤后心功能无法恢复。其中，(A-B)图为4dpt野生型和angpt4突变体的心室体积(A)和mCherry荧光强度(B)统计分析。***：p<0.001。(C-D)图为MTZ处理前后(0-4dpt)野生型和angpt4突变体的心室面积改变分数(C)和心房面积改变分数(D)。面积改变分数＝(舒张面积-收缩面积)/舒张面积。*：p<0.05。
图6：angpt4突变体成体心脏再生受阻。其中，(A)图为野生型和angpt4突变体成鱼60dpi时的冰冻切片马松三色染色结果。灰色虚线代表伤口区域。(B)图为野生型和angpt4突变体成鱼60dpi时心室纤维化瘢痕区域大小的统计结果。angpt4突变体损伤区域的纤维化瘢痕组织显著大于野生型。(C)图为DMSO处理和Tie2抑制剂处理成鱼30dpi时的冰冻切片马松三色染色结果。灰色虚线代表伤口区域。(D)图为DMSO和Tie2抑制剂处理成鱼30dpi时心室纤维化瘢痕区域大小的统计结果。Tie2抑制剂处理后纤维化瘢痕组织显著增大。标尺：100μm。**：p<0.01。
图7：angpt4在斑马鱼胚胎心脏再生过程中的表达谱。在MTZ处理后1-4dpt和其对应发育时期(4-7dpf)对angpt4进行全胚胎原位杂交染色的结果。箭头指示在1dpt的心脏中能够检测到明显的angpt4的mRNA信号。标尺：100μm。
图8：成体斑马鱼心脏再生过程中angpt4的表达变化。冷冻损伤后1、3、7、14、30dpi及假手术(Sham)的心脏冰冻切片angpt4原位杂交。与Sham相比，angpt4的mRNA信号在1dpi开始上升，3dpi时最高，7dpi之后开始下降至30dpi时达到损伤前水平。灰色虚线代表伤口区域。标尺：100μm。
图9：过表达angpt4促进斑马鱼心脏再生。其中，(A)图为荧光图展示Tg(cmlc2:EGFP-angpt4)转基因鱼系3dpf的EGFP信号。标尺：50μm。(B)图为荧光定量PCR结果显示angpt4在Tg(cmlc2:EGFP-angpt4)中显著上调。**：p<0.01。(C)图为野生型和angpt4突变体成鱼60dpi时的冰冻切片马松三色染色结果。灰色虚线代表伤口区域。标尺：100μm。(D)图为野生型和angpt4突变体成鱼30dpi时心室纤维化瘢痕区域大小的统计结果。过表达angpt4的斑马鱼损伤区域的纤维化瘢痕组织显著小于野生型。**：p<0.01。
图10：重组ANGPT4蛋白促进乳大鼠心肌细胞增殖。其中，(A，B)荧光图展示重组ANGPT4蛋白处理后乳大鼠心肌细胞Ki67或Aurora B染色，α-Actinin染色标记心肌细胞，图中亮色为Ki67或Aurora B信号。标尺：50μm。(C，D)图为不同浓度重组ANGPT4蛋白处理后，乳大鼠心肌细胞Ki67或Aurora B阳性比例统计结果。*：p<0.05；***：p<0.001。
图11：过表达ANGPT4促进小鼠心肌细胞增殖和损伤后功能恢复。图中，(A)图展示Western Blot检测AAV9-ANGPT4或AAV9-GFP注射后三周，小鼠心脏中ANGPT4或GFP的表达。(B)图为过表达GFP或ANGPT4三周后石蜡切片马松三色染色结果，未损伤情况下过表达ANGPT4不影响心脏正常形态。标尺：1000μm。(C)荧光图展示注射AAV9-ANGPT4的小鼠，MI手术2周后Ki67或Aurora B染色结果。cTnT染色标记心肌细胞，图中亮色为Ki67或Aurora B信号。标尺：100μm。(D)图为注射AAV9-ANGPT4或AAV9-GFP的小鼠，MI手术2周后心肌细胞Ki67或Aurora B阳性比例统计结果。*：p<0.05；***：p<0.001。(E)图展示超声结果显示注射AAV9-ANGPT4的小鼠心脏功能恢复较注射AAV9-GFP的小鼠更好。EF:射血分数；FS：缩短分数。Delta％EF表示MI后6周比2周EF的改变数值。Delta％FS表示MI后6周比2周FS的改变数值。*：p<0.05。
具体实施方式
以下实施例用于说明本发明，但不用来限制本发明的范围。
实施例中未注明具体技术或条件者，按照本领域内的文献所描述的技术或条件，或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者，均为可通过正规渠道商购买得到的常规产品。
实施例1 ANGPT4蛋白的功能发现及其在斑马鱼中的功能验证
为了揭示心脏再生过程中的整体分子调控网络，以期寻找能够促进心脏再生的潜在靶点，本发明首先以斑马鱼为模式动物，利用双转基因鱼系Tg(vmhc:mCherry-NTR；amhc:EGFP)诱导心室心肌细胞的特异性损伤，并在损伤后的四个时期和其对应的正常发育时期选取单细胞进行单细胞测序。本发明首先利用所有的心脏细胞进行t分布随机邻接嵌入(t-distributed stochastic neighbor embedding，t-SNE)分析，发现了五种主要的细胞群(图1中A图)。结合已知的心脏经典标记基因，本发明发现这五种细胞类型分别是心房心肌细胞(CM-A)、心室心肌细胞(CM-V)、心内皮细胞(EC)、心外膜细胞(EP)和心外膜衍生细胞(EPDC)(图1中B图)。
已报道的大部分研究主要关注的是调控心肌细胞增殖的基因与信号通路，而心脏中不同类型的细胞是如何共同协作以实现完美再生的尚不明确。非心肌细胞在心脏再生过程中能够提供各种各样的信号，参与形成细胞-细胞之间的调控网络，发挥着十分重要的作用(Gonzalez-Rosa et al.,2011；Kikuchi et al.,2011；Lepilina et al.,2006)。本发明进一步挑选发育和再生过程中的非心肌细胞，进行t-SNE分析。结合已知的经典标记基因，本发明发现非心肌细胞可以分为5个亚群，分别是EC、EP、心外膜衍生细胞群1(EPDC-C1)、心外膜衍生细胞群2(EPDC-C2)和增殖祖细胞群(PC)(图2中A图)。进一步地，本发明发现EPDC-C1同时包括发育和再生状态下的细胞，而EPDC-C2只由MTZ(甲硝唑)处理的细胞构成(图2中B图)。本发明把这群再生特异的EPDC细胞群定义为再生特异细胞群(regeneration-induced cell population，RIC)，并利用CRISPR/Cas9系统构建嵌合突变体，进一步筛选在RIC中高表达的基因(Wu et al.，2018)。
在这些基因中，本发明发现angpt4的F0嵌合突变体具有明显的心脏再生缺陷的表型。斑马鱼angpt4基因有两种转录本，编码的ANGPT4蛋白分别包含496或499个氨基酸(其序列如SEQ ID No.1所示)，主要功能结构域包括C端纤维蛋白原结构域，参与调控血管新生。为了进一步探究angpt4在斑马鱼心脏再生中的功能，本发明在angpt4的第1个外显子上设计了gRNA，靶点序列为GGGAACGGTCAAGGGAGACGCGG(SEQ ID No.2，序列末尾的“CGG”为PAM区序列)，并筛选得到了2-bp的缺失突变。突变位点之后的angpt4转录本发生移码突变，并且产生一个提前的终止密码子，进而导致形成一个仅有123个氨基酸残基的无功能的ANGPT4蛋白。
angpt4的纯合突变体可以存活并且可育。与野生型斑马鱼相比，angpt4突变体的胚胎形态、胚胎存活率和产卵数均没有显著差异(图3中A图-C图)。此外，angpt4突变体具有正常的心脏形态。与野生型斑马鱼相比，angpt4突变体的心室最大截面积和心脏重量也没有显著差异(图3中D图-F图)。该结果表明angpt4突变不影响斑马鱼的心脏发育。
本发明利用MTZ处理Tg(amhc:EGFP；vmhc:mCherry-NTR)的野生型和angpt4突变体胚胎，使心室心肌细胞特异性损伤。在野生型中，处理后一天(1day post treatment，dpt)时心室荧光显著减弱，腔室结构消失，几乎不搏动。之后心室逐渐开始恢复，在3dpt时出现腔室结构并开始搏动，并在4dpt时基本恢复损伤前的水平(图4中A图)。与野生型相比，在MTZ处理前(3dpf)，angpt4突变体的心脏没有明显的差异，再次验证了angpt4对心脏的发育没有影响。但是在MTZ处理过后，82枚野生型胚胎中有71枚可以很好地再生损伤的心室，而80枚angpt4突变的胚胎仅有15枚可以再生(图4中B图)。
进一步地，本发明统计了野生型和angpt4突变体胚胎4dpt时的心室体积和mCherry的荧光强度，以及心脏再生过程中(0-4dpt)的心脏功能面积改变(fractionalarea change)。结果显示，与野生型相比，angpt4突变体心室功能在损伤后不能恢复，而心房的功能不受影响(图5)。这些结果表明angpt4对于斑马鱼胚胎心脏的再生具有十分重要的作用。
为了验证angpt4是否对于成体斑马鱼心脏再生是必需的，本发明对野生型和angpt4突变体成鱼进行心室冷冻损伤，并在损伤后60天(60days post injury，dpi)时取出心脏进行冰冻切片。通过对其中最具代表性的切片进行马松三色染色，观察到60dpi时angpt4突变体伤口处纤维化的瘢痕组织显著大于野生型。类似的，抑制ANGPT4下游受体Tie2的活性同样导致瘢痕组织增大(图6)。这表明Tie2在心脏再生过程中十分重要，激活Tie2活性可能可以促进心脏再生能力。
以上结果表明，angpt4突变特异地阻遏了斑马鱼胚胎和成体的心脏再生，而不影响正常的发育过程。为了进一步证明这一结论，本发明首先采用整体胚胎原位杂交技术检测了angpt4在心脏再生前后与再生过程中的表达图谱。结果显示，MTZ处理后1天(1dpt)即可在心脏区域检测到angpt4的明显表达，之后angpt4的mRNA信号逐渐下降，并在损伤后4天完全消失，这与心脏完成再生的时间一致(图7)。相反，在正常发育(未经MTZ处理)的胚胎中则检测不到angpt4的表达。
进一步地，本发明通过冰冻切片原位杂交的方法检测了angpt4在斑马鱼心脏冷冻损伤后不同时期的转录水平。收集斑马鱼心脏冷冻损伤后1、3、7、14、30天(dpi)以及假手术(Sham)的心脏进行冰冻切片，并利用angpt4的探针进行原位杂交。结果显示，在假手术的心脏中基本检测不到angpt4的表达(图8)。冷冻损伤后，angpt4的mRNA最早可以在1dpi时检测到在伤口区域表达，在3dpi时达到最高水平的表达，之后逐渐开始下降，并在30dpi再生基本完成时达到损伤前的水平。这些结果与之前的实验结果相吻合，即angpt4特异在受损的心室中被诱导表达，很可能只在心脏再生中发挥作用。
为了进一步探究angpt4能否促进斑马鱼的心脏再生能力，本发明构建了Tg(cmlc2:EGFP-angpt4)转基因鱼系，在心肌细胞中持续性表达angpt4。在3dpf的转基因胚胎中可以检测到明显的EGFP信号(图9中A图)。荧光定量PCR结果同样显示angpt4在转基因胚胎中显著上调，证明了转基因鱼系过表达angpt4的有效性(图9中B图)。继而在转基因斑马鱼中进行了心室冷冻损伤手术，并在手术后30天统计瘢痕组织大小。结果发现，过表达angpt4的斑马鱼相较于野生型瘢痕组织显著减少(图9中C图，D图)。
实施例2 ANGPT4蛋白在哺乳动物中的功能验证
为了进一步探究ANGPT4促进心脏再生的能力是否在哺乳动物中保守，本发明首先通过体外培养乳大鼠心肌细胞(neonatal rat cardiomyocyte，NRCM)的方式进行检测。在乳大鼠心肌细胞的培养体系中加入不同浓度的重组人源ANGPT4蛋白(氨基酸序列如SEQ IDNo.3所示)，并且检测心肌细胞增殖能力。结果发现，ANGPT4蛋白处理可以显著促进乳大鼠心肌细胞Ki67和Aurora B阳性比例，并且ANGPT4浓度越高促进程度越强(图10)。以上结果表明ANGPT4促进心肌细胞增殖的能力在哺乳动物中是高度保守的。
为了进一步探究ANGPT4能否在体内促进哺乳动物心脏功能恢复，本发明构建了过表达人源ANGPT4基因的腺相关病毒9载体(adeno-associated virus 9，AAV9)，同时构建了过表达GFP的病毒载体作为对照。通过尾静脉注射的方式将病毒注入成年雄性小鼠(6-8周龄)的循环系统。在尾静脉注射后3周，可以在小鼠的心脏中检测到ANGPT4或EGFP信号，表明腺相关病毒成功感染了小鼠心脏组织(图11中A图)。对过表达三周后小鼠马松三色染色结果显示，未损伤情况下过表达ANGPT4不影响心脏形态(图11中B图)。继而对注射ANGPT4和GFP的小鼠进行了心肌梗塞(myocardial infraction，MI)手术。本发明首先在术后两周通过Ki67和Aurora B染色，来评估小鼠心肌细胞的增殖能力。结果显示，与GFP对照组相比，ANGPT4过表达组的心肌细胞具有明显更高的增殖能力(图11中C图，D图)。更有意思的是，本发明通过超声检测小鼠的射血分数(ejection fraction，EF)和缩短分数(fractionalshortening，FS)发现，与GFP对照组相比，ANGPT4过表达组损伤后的心脏功能恢复到了更高的水平(图11中E图)。
虽然，上文中已经用一般性说明及具体实施方案对本发明作了详尽的描述，但在本发明基础上，可以对之作一些修改或改进，这对本领域技术人员而言是显而易见的。因此，在不偏离本发明精神的基础上所做的这些修改或改进，均属于本发明要求保护的范围。
序列表
<110> 北京大学
<120> ANGPT4蛋白及其编码基因在调控心脏损伤后的修复与再生能力中的应用
<130> KHP211117036.2
<160> 3
<170> SIPOSequenceListing 1.0
<210> 1
<211> 496
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 1
Met Arg Leu Ala Arg Ser Gly Trp His Leu Ala Leu Leu Leu Leu Ala
1 5 10 15
Trp Val Asn Leu Ala Ser Ser Gly Asn Gly Asn Gly Gln Gly Arg Arg
20 25 30
Gly Gly Gly Gly Glu Arg Arg Arg Lys Leu His Arg Val Gln Asn Gly
35 40 45
Gln Cys Ser Tyr Thr Phe Ile Leu Pro Glu Met Glu Ser Cys Gln Glu
50 55 60
Gln Met Ser Gly Thr His Gly Val Gln Arg Asp Ser Pro Pro Ala Asp
65 70 75 80
Ser Glu Trp Ser Val Gln Lys Leu Gln His Leu Glu Thr Ala Met Glu
85 90 95
Asn Asn Thr Gln Trp Leu Gln Lys Leu Glu Asn Tyr Ile Glu Gln Lys
100 105 110
Thr Gly Met Val His Ile Gln Ala Asp Ala Val His Asn Gln Thr Ala
115 120 125
Thr Met Leu Glu Ile Gly Thr Asn Leu Leu Ser Gln Thr Ala Glu Gln
130 135 140
Ser Arg Lys Leu Asn Val Val Glu Ala Lys Val Met Asn Gln Thr Ser
145 150 155 160
Arg Ile Ala Ile Gln Leu Leu Glu Asn Ser Leu Ser Thr Asn Lys Leu
165 170 175
Glu Lys Glu Leu Ile Ser Gln Leu Ser Glu Ile Ser Lys Leu Arg Asp
180 185 190
Lys Asn Ser His Leu Glu Ser Lys Val Leu Val Leu Glu Ser Gln Gln
195 200 205
Arg Thr Glu Leu Glu Asp Met Arg Glu Glu Lys Glu Arg Leu Gln Asp
210 215 220
Leu Val Lys Arg Gln Thr Ala Ala Ile Thr Ala Leu Glu Arg Gln Leu
225 230 235 240
Arg Ala Ala Ser Ser Asn Asn Ser Ala Leu Gln Lys Gln His Gln Gln
245 250 255
Leu Met Lys Ser Val His Thr Leu Ile Gly Met Val Ser Ser Gly Thr
260 265 270
Gly Ile Thr Pro Asn Glu Gln Arg Phe Arg Asp Cys Ala Glu Ala Tyr
275 280 285
Lys Ser Gly His Asn Thr Ser Gly Val Tyr His Ile Tyr Ile Gly Asp
290 295 300
Met Thr Glu Pro Thr Lys Val Phe Cys Asp Met Val Thr Ser Gly Gly
305 310 315 320
Gly Trp Thr Val Phe Gln His Arg Ala Asn Gly Ser Val Asn Phe Gln
325 330 335
Lys Gly Trp Lys Asp Tyr Lys Leu Gly Phe Gly Asp Pro Ser Gly Glu
340 345 350
His Trp Leu Gly Asn Glu Ala Ile His Leu Ile Thr Ser Gln Gly Gln
355 360 365
Tyr Ser Leu Arg Val Glu Leu Lys Asp Trp Glu Glu Asn Gly Ala Tyr
370 375 380
Ala Leu Tyr Asp Lys Phe Gln Leu Thr Ser Glu Lys Gln Gln Tyr Arg
385 390 395 400
Leu Leu Leu Gly Ser His Ser Gly Thr Ala Gly Gln Lys Ser Ser Leu
405 410 415
Ala Leu Asn Gly Thr Gly Phe Ser Thr Arg Asp Ala Asp Asn Asp Lys
420 425 430
Cys Glu Cys Lys Cys Ala Leu Met Met Thr Gly Gly Trp Trp Phe Glu
435 440 445
Ala Cys Gly Met Ser Asn Leu Asn Gly Ile Tyr Tyr Thr Ile Gly His
450 455 460
Asn Ile Arg Lys Leu Asn Gly Ile Lys Trp His His Phe Arg Gly Pro
465 470 475 480
Ser Tyr Ser Leu Gln Ser Thr Ser Met Met Ile Arg Pro Thr Asp Phe
485 490 495
<210> 2
<211> 23
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 2
gggaacggtc aagggagacg cgg 23
<210> 3
<211> 503
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 3
Met Leu Ser Gln Leu Ala Met Leu Gln Gly Ser Leu Leu Leu Val Val
1 5 10 15
Ala Thr Met Ser Val Ala Gln Gln Thr Arg Gln Glu Ala Asp Arg Gly
20 25 30
Cys Glu Thr Leu Val Val Gln His Gly His Cys Ser Tyr Thr Phe Leu
35 40 45
Leu Pro Lys Ser Glu Pro Cys Pro Pro Gly Pro Glu Val Ser Arg Asp
50 55 60
Ser Asn Thr Leu Gln Arg Glu Ser Leu Ala Asn Pro Leu His Leu Gly
65 70 75 80
Lys Leu Pro Thr Gln Gln Val Lys Gln Leu Glu Gln Ala Leu Gln Asn
85 90 95
Asn Thr Gln Trp Leu Lys Lys Leu Glu Arg Ala Ile Lys Thr Ile Leu
100 105 110
Arg Ser Lys Leu Glu Gln Val Gln Gln Gln Met Ala Gln Asn Gln Thr
115 120 125
Ala Pro Met Leu Glu Leu Gly Thr Ser Leu Leu Asn Gln Thr Thr Ala
130 135 140
Gln Ile Arg Lys Leu Thr Asp Met Glu Ala Gln Leu Leu Asn Gln Thr
145 150 155 160
Ser Arg Met Asp Ala Gln Met Pro Glu Thr Phe Leu Ser Thr Asn Lys
165 170 175
Leu Glu Asn Gln Leu Leu Leu Gln Arg Gln Lys Leu Gln Gln Leu Gln
180 185 190
Gly Gln Asn Ser Ala Leu Glu Lys Arg Leu Gln Ala Leu Glu Thr Lys
195 200 205
Gln Gln Glu Glu Leu Ala Ser Ile Leu Ser Lys Lys Ala Lys Leu Leu
210 215 220
Asn Thr Leu Ser Arg Gln Ser Ala Ala Leu Thr Asn Ile Glu Arg Gly
225 230 235 240
Leu Arg Gly Val Arg His Asn Ser Ser Leu Leu Gln Asp Gln Gln His
245 250 255
Ser Leu Arg Gln Leu Leu Val Leu Leu Arg His Leu Val Gln Glu Arg
260 265 270
Ala Asn Ala Ser Ala Pro Ala Phe Ile Met Ala Gly Glu Gln Val Phe
275 280 285
Gln Asp Cys Ala Glu Ile Gln Arg Ser Gly Ala Ser Ala Ser Gly Val
290 295 300
Tyr Thr Ile Gln Val Ser Asn Ala Thr Lys Pro Arg Lys Val Phe Cys
305 310 315 320
Asp Leu Gln Ser Ser Gly Gly Arg Trp Thr Leu Ile Gln Arg Arg Glu
325 330 335
Asn Gly Thr Val Asn Phe Gln Arg Asn Trp Lys Asp Tyr Lys Gln Gly
340 345 350
Phe Gly Asp Pro Ala Gly Glu His Trp Leu Gly Asn Glu Val Val His
355 360 365
Gln Leu Thr Arg Arg Ala Ala Tyr Ser Leu Arg Val Glu Leu Gln Asp
370 375 380
Trp Glu Gly His Glu Ala Tyr Ala Gln Tyr Glu His Phe His Leu Gly
385 390 395 400
Ser Glu Asn Gln Leu Tyr Arg Leu Ser Val Val Gly Tyr Ser Gly Ser
405 410 415
Ala Gly Arg Gln Ser Ser Leu Val Leu Gln Asn Thr Ser Phe Ser Thr
420 425 430
Leu Asp Ser Asp Asn Asp His Cys Leu Cys Lys Cys Ala Gln Val Met
435 440 445
Ser Gly Gly Trp Trp Phe Asp Ala Cys Gly Leu Ser Asn Leu Asn Gly
450 455 460
Val Tyr Tyr His Ala Pro Asp Asn Lys Tyr Lys Met Asp Gly Ile Arg
465 470 475 480
Trp His Tyr Phe Lys Gly Pro Ser Tyr Ser Leu Arg Ala Ser Arg Met
485 490 495
Met Ile Arg Pro Leu Asp Ile
500
Claims (13)
1.ANGPT4蛋白、或其转录本、或其编码基因、或含有其编码基因的生物材料、或其关键结构域其C端纤维蛋白原结构域、或其表达促进剂、或其表达抑制剂、或其突变体、或其下游受体促进剂、或其下游受体抑制剂在以下至少一方面的应用：
a)在调控动物或人心脏损伤后的修复与再生能力中的应用；
b)在制备用于调控动物或人心脏损伤后的修复与再生能力的药物中的应用。
2.ANGPT4蛋白、或其转录本、或其编码基因、或含有其编码基因的生物材料、或其关键结构域、或其表达促进剂、或其下游受体促进剂在以下至少一方面的应用：
a)在预防、减缓、治疗与动物或人心脏损伤相关的疾病或使所述疾病消退中的应用；
b)在制备用于预防、减缓、治疗与动物或人心脏损伤相关的疾病或使所述疾病消退的药物中的应用；
c)在减少动物或人心脏损伤后纤维化的瘢痕组织中的应用；
d)在制备用于减少动物或人心脏损伤后纤维化的瘢痕组织的药物中的应用；
优选所述疾病为心肌细胞损伤、坏死或凋亡所导致的疾病；更优选所述疾病为缺血性心脏病；进一步优选所述疾病为心肌梗塞。
3.ANGPT4蛋白或其编码基因、或含有其编码基因的生物材料或其关键结构域在以下至少一方面的应用：
a)在预测动物或人心脏损伤后的修复与再生能力中的应用；
b)在制备用于预测动物或人心脏损伤后的修复与再生能力的试剂或试剂盒中的应用；
c)在检测动物或人心脏损伤情况中的应用；
d)在制备用于检测动物或人心脏损伤情况的试剂或试剂盒中的应用。
4.根据权利要求1或2所述的应用，其特征在于，所述药物通过调控心肌细胞的增殖能力和/或激活内皮细胞中的Tie2-MAPK信号通路来实现对心脏损伤后的修复与再生能力的调控。
5.根据权利要求1或2所述的应用，其特征在于，所述下游受体为Tie2。
6.根据权利要求1-5中任一项所述的应用，其特征在于，所述心脏损伤具体为心室损伤；和/或，所述动物为哺乳动物。
7.根据权利要求1-6中任一项所述的应用，其特征在于，所述ANGPT4蛋白或其编码基因源自灵长目、啮齿目、偶蹄目或鲤形目的物种；优选其源自人、猴、小鼠、大鼠、猪或斑马鱼；
优选地，所述ANGPT4蛋白具有以下任意一种氨基酸序列：
1)SEQ ID NO.1或3所示的氨基酸序列；或
2)SEQ ID NO.1或3所示的氨基酸序列经过一个或多个氨基酸残基的替换、缺失或插入获得的具有相同功能蛋白的氨基酸序列。
8.一种非治疗目的的促进心肌细胞增殖的方法，其特征在于，其包括在心肌细胞内表达或过表达ANGPT4蛋白；
所述表达或过表达ANGPT4蛋白的方式包括：在所述心肌细胞中导入表达或过表达ANGPT4蛋白的载体，和/或，对心肌细胞施用ANGPT4蛋白的表达促进剂；然后对心肌细胞进行体外培养。
9.一种非治疗目的的抑制心肌细胞增殖的方法，其特征在于，其包括在心肌细胞内抑制或消除ANGPT4蛋白的表达；
所述抑制或消除ANGPT4蛋白的表达的方式包括：在所述心肌细胞中导入抑制或消除ANGPT4蛋白表达的载体，和/或，对心肌细胞施用ANGPT4蛋白的表达抑制剂；然后对心肌细胞进行体外培养。
10.一种心脏再生缺陷动物模型的构建方法，其特征在于，其包括在对象中抑制ANGPT4蛋白的编码基因的表达，所述抑制可以是心脏特异性的或全局性的。
11.一种生物材料，其特征在于，其含有ANGPT4蛋白的编码基因；所述生物材料选自表达盒、载体、宿主细胞和重组菌的一种或多种。
12.一种药物组合物，其特征在于，其含有：
ANGPT4蛋白、或其转录本、或其编码基因、或含有其编码基因的生物材料、或其关键结构域、或其表达促进剂、或其下游受体促进剂中的一种或多种；
以及，药学上可接受、且辅助其用于以下至少一种用途的辅料：1)预防、减缓、治疗与动物或人心脏损伤相关的疾病或使所述疾病消退；2)减少动物或人心脏损伤后纤维化的瘢痕组织。
13.一种试剂盒，其特征在于，其含有用于检测ANGPT4蛋白或其编码基因、或含有其编码基因的生物材料、或其关键结构域中的一种或多种物质的试剂；以用于以下至少一种用途：1)预测动物或人心脏损伤后的修复与再生能力；2)检测动物或人心脏损伤情况。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111064028.8A CN113956345B (zh) | 2021-09-10 | 2021-09-10 | Angpt4蛋白及其编码基因在调控心脏损伤后的修复与再生能力中的应用 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111064028.8A CN113956345B (zh) | 2021-09-10 | 2021-09-10 | Angpt4蛋白及其编码基因在调控心脏损伤后的修复与再生能力中的应用 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN113956345A true CN113956345A (zh) | 2022-01-21 |
| CN113956345B CN113956345B (zh) | 2024-04-23 |
Family
ID=79461311
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202111064028.8A Active CN113956345B (zh) | 2021-09-10 | 2021-09-10 | Angpt4蛋白及其编码基因在调控心脏损伤后的修复与再生能力中的应用 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113956345B (zh) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20070141632A1 (en) * | 2003-05-29 | 2007-06-21 | The Trustees Of The University Of Pennsylvania | Function and regulation of angiopoietin-3/angiopoietin-4 |
| CN101186643A (zh) * | 2007-11-30 | 2008-05-28 | 宁夏回族自治区水产研究所 | 一种动物心肌性能相关蛋白及其编码基因与应用 |
| CN111440795A (zh) * | 2013-12-24 | 2020-07-24 | Ionis制药公司 | 促血管生成素样3表达的调节 |
-
2021
- 2021-09-10 CN CN202111064028.8A patent/CN113956345B/zh active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20070141632A1 (en) * | 2003-05-29 | 2007-06-21 | The Trustees Of The University Of Pennsylvania | Function and regulation of angiopoietin-3/angiopoietin-4 |
| CN101186643A (zh) * | 2007-11-30 | 2008-05-28 | 宁夏回族自治区水产研究所 | 一种动物心肌性能相关蛋白及其编码基因与应用 |
| CN111440795A (zh) * | 2013-12-24 | 2020-07-24 | Ionis制药公司 | 促血管生成素样3表达的调节 |
Non-Patent Citations (2)
| Title |
|---|
| GENBANK: "angiopoietin-1[Danio rerio]", 《GENBANK DATABASE》 * |
| GENBANK: "angiopoietin-4 isoform 1 precursor[Homo sapiens]", 《GENBANK DATABASE》 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN113956345B (zh) | 2024-04-23 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN110730823B (zh) | 组织选择性转基因表达 | |
| Ivanov et al. | Cerebellar ataxia, seizures, premature death, and cardiac abnormalities in mice with targeted disruption of the Cacna2d2 gene | |
| Lee et al. | Platelet-derived growth factor-C and-D in the cardiovascular system and diseases | |
| Shen et al. | Mononuclear diploid cardiomyocytes support neonatal mouse heart regeneration in response to paracrine IGF2 signaling | |
| CA2404616C (en) | Use of vegf and homologues to treat neuron disorders | |
| RU2251838C2 (ru) | Способ получения неприродной трансгенной мыши с дефицитом гена рецептора 2 кортиколиберина и ее использование | |
| KR20220131262A (ko) | 섬유증, 비대 또는 심부전의 치료 또는 예방에 사용하기 위한 골수-유래 성장 인자 | |
| US20150164957A1 (en) | Conversion of cardiomyocytes into fast conducting cardiomyocytes or slow conducting nodal cells | |
| US7345158B2 (en) | Actin related cytoskeletal protein “LACS” | |
| Hui et al. | FBXW5 acts as a negative regulator of pathological cardiac hypertrophy by decreasing the TAK1 signaling to pro-hypertrophic members of the MAPK signaling pathway | |
| KR101133289B1 (ko) | Ａｋａｐ１２를 함유하는 조성물 및 동물 모델로서ａｋａｐ１２ 돌연변이 제브라피쉬의 용도 | |
| CN113956345B (zh) | Angpt4蛋白及其编码基因在调控心脏损伤后的修复与再生能力中的应用 | |
| JP2000506373A (ja) | ＴＧＦβシグナル伝達たんぱく質、遺伝子およびその用途 | |
| KR20240032021A (ko) | 신경 재프로그래밍을 위한 방법 및 조성물 | |
| KR102236843B1 (ko) | 새로운 재생 치료제로서의 camkk1 | |
| KR20160048103A (ko) | Vegf-c 및 ccbe1의 치료적 용도 | |
| WO2014191630A2 (en) | Non-human animal model encoding a non-functional manf gene | |
| US8450274B2 (en) | DKK2 protein and use thereof | |
| EP2042189B1 (en) | Use of proinsulin for the preparation of a neuroprotective pharmaceutical composition, therapeutic composition containing it and applications thereof | |
| AU736492B2 (en) | Vertebrate embryonic pattern-inducing hedgehog-like proteins | |
| WO2024006898A2 (en) | Gene therapy of hippo signaling improves heart function in a clinically relevant model | |
| JP2002543767A (ja) | 生殖細胞と体細胞が４ｅ−ｂｐ１をコードするｄｎａにノックアウト突然変異を含有する非ヒトトランスジェニック動物 | |
| JP6587091B2 (ja) | 寿命短縮化モデル非ヒト哺乳動物 | |
| JP2022530168A (ja) | 心臓保護的活性のあるタンパク質 | |
| Paldino | TITIN DOWNREGULATION AFFECTS CARDIOMYOCYTES PROLIFERATION |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant |