CN114487429A - Application of urine protein delta homolog 1 and polypeptide fragment thereof in gestational diabetes - Google Patents
Application of urine protein delta homolog 1 and polypeptide fragment thereof in gestational diabetes Download PDFInfo
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Abstract
The invention provides application of urine Protein delta homolog 1 (DLK 1) and polypeptide fragments thereof, in particular to application of urine Protein delta homolog 1 and polypeptide fragments thereof in preparation of preparations for diagnosis and treatment of gestational diabetes patients, monitoring and evaluation of blood sugar and metabolic states, mechanism research and the like. The research proves that the urine protein delta congener 1 and the polypeptide fragment thereof are reduced along with the rise of the HbA1c level in the gestational diabetes patients, have statistical significance in the difference between the BM1 group with the HbA1c being less than or equal to 5.1% and the BM2 group with the HbA1c being more than 5.1%, and can be used for diagnosis and treatment of the gestational diabetes patients, monitoring, evaluation, mechanism research and other purposes and application detection. The invention exerts the advantages of non-invasive acquisition, large-scale repeated sampling and convenient preservation of the urine specimen, and utilizes the urine specimen to detect the protein delta homolog 1 and the polypeptide fragment thereof.
Description
Technical Field
The invention relates to a new application of urine protein delta congener 1 and a polypeptide fragment thereof, in particular to an application of urine protein delta congener 1 and a polypeptide fragment thereof in preparations for diagnosis and treatment of gestational diabetes patients, monitoring, evaluation and mechanism research of blood sugar and metabolic state and the like.
Background
The pathogenesis of Gestational Diabetes Mellitus (GDM) is mainly that the pregnant women have increased glucose demand, insulin resistance and relatively insufficient insulin secretion, etc. The incidence of adverse pregnancy outcomes of GDM patients with poor blood sugar control, such as abortion in pregnancy, premature delivery, cesarean section, hypertension, and the like, is obviously higher than that of normal pregnant women, and the incidence of adverse complications of hypoglycemia, hypoimmunity, megaly, neonatal hyperbilirubinemia, neonatal respiratory distress syndrome, asphyxia, and the like, of newborns delivered by GDM patients is also obviously increased. In view of the fact that GDM can generate a plurality of bad prognoses for mothers and babies, the clinical advantages of urine proteomics are expected to be applied, and the biomarkers capable of reflecting the glucose metabolism control state in the body of a GDM patient and the glucose metabolism and growth and development conditions of fetuses are searched by combining with common clinical indexes such as fasting blood glucose and glycosylated hemoglobin, so that the damage caused by the hypoglycemia of newborns is prevented and reduced, the incidence rate of the giant infants is reduced, and a foundation is laid for the research of a urine polypeptide detection kit.
Protein delta homolog 1 (DLK 1) is encoded by the DLK1 gene and is found in mesenchymal cells in intimate contact with placental villi, yolk sac, fetal liver, adrenal cortex and pancreatic vasculature, as well as in adult pancreatic islet beta cells. Levels of circulating and membrane line DLK1 are physiologically upregulated during embryogenesis, lactation and pregnancy. Studies report that DLK1 negatively regulates lipogenesis, shifts the body's metabolic pattern to peripheral lipid oxidation, away from lipid stores, mediates important physiological processes associated with early life, and has an effect on metabolic disease resistance. Increasing the dose of DLK1 improves glucose tolerance by modulating the growth hormone pathway, and adipose tissue expansion does not appear to be the major defect even under extreme metabolic stress. In the present study, the expression of DLK1 in urine of GDM patients was found to be inversely correlated with HbA1c levels. It is shown that with the aggravation of glucose metabolism disorder of GDM patients, the expression level of DLK1 is reduced, and the ability of improving glucose tolerance and negatively regulating lipogenesis is reduced.
Compared with the common clinical blood sample, the urine can be collected in a non-invasive, continuous and large amount; without homeostatic regulation, more various and larger changes can be accumulated, and many pathophysiological changes of the body can be reflected in urine. Some protein polypeptides with relatively small molecular weight, such as hormones and cytokines, are excreted into urine quickly after entering blood, and the probability that the proteins and polypeptides are detected in urine is much higher than that in blood; before urine is collected, a possible protein degradation process in urine is completed, so that urine protein can be kept stable for a longer time. In order to relieve the pain of multiple blood sampling of GDM patients, the experiment is expected to realize painless, convenient, rapid and easily repeated urine detection to assist the monitoring and evaluation of the GDM patients and the fetal metabolic state through the research of urine protein or polypeptide on the basis of the methodology of the prior stage.
Disclosure of Invention
The invention aims to provide application of urine protein delta homolog 1 and a polypeptide fragment thereof in preparation of preparations for diagnosis and treatment of gestational diabetes patients, monitoring of blood sugar and metabolic state, prognosis, mechanism research and the like.
Preferably, the amino acid sequence of the urine protein delta homolog 1 is shown in SEQ ID NO.1 (MTATEALLRV LLLLLAFGHS TYGAECFPAC NPQNGFCEDD NVCRCQPGWQ GPLCDQCVTS PGCLHGLCGE PGQCICTDGW DGELCDRDVR ACSSAPCANN RTCVSLDDGL YECSCAPGYS GKDCQKKDGP CVINGSPCQH GGTCVDDEGR ASHASCLCPP GFSGNFCEIV ANSCTPNPCE NDGVCTDIGG DFRCRCPAGF IDKTCSRPVT NCASSPCQNG GTCLQHTQVS YECLCKPEFT GLTCVKKRAL SPQQVTRLPS GYGLAYRLTP GVHELPVQQP EHRILKVSMK ELNKKTPLLT EGQAICFTIL GVLTSLVVLG TVGIVFLNKC ETWVSNLRYN HMLRKKKNLL LQYNSGEDLA VNIIFPEKID MTTFSKEAGD EEI); or an amino acid sequence which is derived from the amino acid sequence shown in SEQ ID NO.1 and has the same function with the amino acid sequence shown in SEQ ID NO. 1.
Preferably, the preparation is a urine protein delta homolog 1 of a gestational diabetes patient and a polypeptide fragment detection kit thereof.
Preferably, the kit comprises an immunization method for antigen-antibody reaction and kits thereof such as one or more of an aptamer antibody or antibody fragment capable of specifically binding to protein delta homolog 1 and polypeptide fragments thereof.
Preferably, the kit comprises methods for directly detecting mass spectra of the protein delta homolog 1 and the polypeptide fragment thereof and related kits thereof.
Preferably, the kit comprises related nucleic acid detection methods for directly detecting the protein delta homolog 1 and the polypeptide fragment thereof and related kits thereof.
Preferably, the kit further comprises a component selected from the group consisting of: the kit comprises a solid phase carrier, a diluent, a reference substance, a standard substance, a quality control substance, a detection antibody, a second antibody diluent, a luminescent reagent, a washing solution, a color development solution and a stop solution, wherein the solid phase carrier is any one or a combination of a plurality of the solid phase carrier, the diluent, the reference substance, the standard substance, the quality control substance, the detection antibody, the second antibody and the second antibody diluent.
Preferably, the standard comprises a protein delta homolog 1 standard, a humanized tag antibody standard; preferably, the quality control product comprises: quality control products of the protein delta congener 1 and humanized label antibody; preferably, the solid support comprises: particles, microspheres, glass slides, test strips, plastic beads, liquid phase chips, micro-porous plates or affinity membranes and other carriers with the same functions.
Preferably, the solid phase carrier is made of any one of polyvinyl chloride, polystyrene, polyacrylamide and cellulose, and has similar functions.
The inventor firstly collects urine samples of gestational diabetes patients in the early pregnancy period, centrifuges the urine samples and takes the supernatant, and the supernatant is divided into GM1 and GM2 groups according to the FPG level; HbA1c levels were divided into BM1 and BM2 groups. And purifying and separating the urine specimen by using weak cation exchange magnetic beads. Uniformly mixing 1 mu l of sample and 10 mu l of matrix, taking 1 mu l of point on an Anchorchip target plate, ionizing the sample, carrying out mass spectrometry, and collecting data within the range of 1000-10000Da to obtain a mass spectrometry polypeptide diagram consisting of protein peaks with different mass-to-charge ratios. All mass spectrograms of different groups of gestational diabetes mellitus were analyzed using the BioExplorer analysis software to screen for differential polypeptides. Then, the inventor carries out matrix-assisted laser desorption ionization time-of-flight mass spectrometry identification on the differential polypeptide with statistical significance, and searches a database to obtain the differentially expressed protein delta homolog 1.
The invention proves that the protein delta homolog 1 is reduced along with the increase of the HbA1c level through research, and the difference has statistical significance. Therefore, the detection of the urine protein delta homolog 1 and the polypeptide fragment thereof can be used for diagnosis and treatment of the gestational diabetes patients, monitoring and evaluation of blood sugar and metabolic states and mechanism research.
The invention exerts the advantages of noninvasive acquisition, large-scale repeated sampling and convenient storage of the urine sample, and utilizes the urine sample to detect the protein delta homolog 1 and the polypeptide fragment thereof.
In order to make the aforementioned and other objects, features and advantages of the present invention comprehensible, preferred embodiments accompanied with figures are described in detail below.
Drawings
FIG. 1 is a scatter plot of urine protein delta homolog 1 expression from diabetic patients with pregnancies in the group of BM1 and BM 2.
Detailed Description
Example 1Collection and processing of urine specimens
Clean mid-stream urine specimens of 74 cases of Gestational Diabetes Mellitus (GDM) patients in early pregnancy (8-12 weeks) in obstetrical clinics and hospitalization of Beijing century bed hospitals affiliated to the university of capital medical science are collected and aged 24-42 years. The gestational diabetes mellitus patient accords with the 2011 diabetes diagnosis and treatment standard of American Diabetes Association (ADA), all clinical data from the early pregnancy to 42 days after delivery are complete, and 75g sugar OGTT test is performed at 24-28 weeks of pregnancy. Without the combination of acute and chronic infections, tumors, cardiovascular disease and severe liver and kidney dysfunction, 74 gestational diabetics were classified according to Fasting Plasma Glucose (FPG) and glycated hemoglobin (HbA 1 c) levels: group GM1 (FPG < 4.50 mmol/L) and group GM2 (FPG > 4.50 mmol/L); HbA1c of BM1 group is less than or equal to 5.1 percent; BM2 group HbA1c > 5.1%. After urine collection, 400 Xg centrifugation for 5min, supernatant was collected and split charged and frozen at-80 ℃. Meanwhile, in order to track the urine polypeptide secretion difference of the same GDM patients in the middle and late gestation periods, 30 patients out of 74 GDM patients retained urine samples of the middle gestation period (GDM-M group, 24-27 weeks) and the late gestation period (GDM-L group, 28-41 weeks) at the same time. Clinical characteristics of the subjects are shown in Table 1-1.
TABLE 1-1 general clinical data comparison (X±S）
Note: Alb/Cr means urinary microalbumin to creatinine ratio <30
Example 2Magnetic bead purification and urine polypeptide screening
And enriching the polypeptide in the urine by using weak cation exchange magnetic beads, and analyzing the polypeptide spectrum in the urine by using a matrix assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS). After calibration of the instrument with standards, 1. mu.l of the eluate was mixed with 10. mu.l of matrix (0.3% of. alpha. -cyano-4-hydroxycinnamic acid, HCCA) and 1. mu.l of the spot was applied to an Anchorchip (Autoflex MALDI TOF, Bruker-Dalton) target plate and dried at room temperature. And ionizing the sample by irradiating the nitrogen laser, and then carrying out mass spectrometry, and acquiring data in the range of 1000-10000Da to obtain a mass spectrogram consisting of protein peaks with different mass-to-charge ratios. For each MALDI crystallisation spot, a total of 400 laser shots (50 shots at each of the 8 different positions of each crystallisation spot) were made, and the average represented a sample, thereby obtaining a polypeptide profile for all samples. Three biological replicates were performed per sample. The mass spectra of BM1 and BM2 were analyzed using BioExplorer analysis software to screen for different polypeptides. The polypeptide peak of mass to charge ratio (m/z) 1206 was statistically different between the 2 groups (P < 0.05).
Example 3Statistical analysis
FPG, HbA1c and urine polypeptide markers of GDM patients were correlated using Pearson correlation analysis, with a statistically significant correlation of bilateral correlation P < 0.05. A Fisher discriminant function analysis module of the SPSS is used for establishing a classification discriminant function of the GDM glucose metabolic state and several independent variables of the FPG and HbA1c levels of the GDM patient, the peak value of the urinary peptide biomarker, the neonatal blood glucose (NFPG), the Neonatal Height (NH) and the Neonatal Weight (NW). The primary classification was performed on samples from the GM1 and GM2, BM1 and BM2 groups to determine the diagnostic efficacy of the discriminant analysis function model.
Example 4Identification and analysis of differential Polypeptides
From the sample tube, 20ul was taken for LC-MS/MS analysis. An EASY-nLC1000 HPLC system was used for the separation. Liquid phase a was 0.1% formic acid in acetonitrile (2% acetonitrile) and liquid phase B was 0.1% formic acid in acetonitrile (98% acetonitrile). 100% A solution was equilibrated with a flow rate of 400nl/min on a 100X 100mm BEHnanoACquisity column. The chromatographic spray needle is PN: FS 360-20-10-N-20-C12. Samples were separated by capillary HPLC and analyzed by Q-exact mass spectrometer (Thermo). The ion source voltage is 3.5kv, the analysis time is 120min, and the scanning range of the parent ion is 300-2000 m/z. The mass-to-charge ratios of the polypeptides and polypeptide fragments were collected by collecting 20 fragments (MS 2scan, HCD) after each complete scan. At M/Z200, the MS1 resolution was 70,000, and the MS2 resolution was 17,500. Data analysis software PD (Proteome discovery 1.4, thermo) was used for the search. The search database is Mascot. The parent ion error was set to 20ppm, the fragment ion error was set to 1Da, the digestion mode was non-digestion, and the modification was oxidation (M) of methionine. Data card value, Percolator algorithm, FDR < 1%. The differentially expressed polypeptide peak of mass to charge (m/z) 1260 was retrieved in the database and identified as protein delta homolog 1.
Although the present invention has been described with respect to the preferred embodiments, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims.
Sequence listing
<110> Beijing century bed Hospital affiliated to capital medical university
<120> application of urine protein delta homolog 1 and polypeptide fragment thereof in gestational diabetes
<130> 20PDLK1-CN
<141> 2020-11-12
<160> 1
<170> SIPOSequenceListing 1.0
<210> 1
<211> 383
<212> PRT
<213> human urine
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Met Thr Ala Thr Glu Ala Leu Leu Arg Val Leu Leu Leu Leu Leu Ala
1 5 10 15
Phe Gly His Ser Thr Tyr Gly Ala Glu Cys Phe Pro Ala Cys Asn Pro
20 25 30
Gln Asn Gly Phe Cys Glu Asp Asp Asn Val Cys Arg Cys Gln Pro Gly
35 40 45
Trp Gln Gly Pro Leu Cys Asp Gln Cys Val Thr Ser Pro Gly Cys Leu
50 55 60
His Gly Leu Cys Gly Glu Pro Gly Gln Cys Ile Cys Thr Asp Gly Trp
65 70 75 80
Asp Gly Glu Leu Cys Asp Arg Asp Val Arg Ala Cys Ser Ser Ala Pro
85 90 95
Cys Ala Asn Asn Arg Thr Cys Val Ser Leu Asp Asp Gly Leu Tyr Glu
100 105 110
Cys Ser Cys Ala Pro Gly Tyr Ser Gly Lys Asp Cys Gln Lys Lys Asp
115 120 125
Gly Pro Cys Val Ile Asn Gly Ser Pro Cys Gln His Gly Gly Thr Cys
130 135 140
Val Asp Asp Glu Gly Arg Ala Ser His Ala Ser Cys Leu Cys Pro Pro
145 150 155 160
Gly Phe Ser Gly Asn Phe Cys Glu Ile Val Ala Asn Ser Cys Thr Pro
165 170 175
Asn Pro Cys Glu Asn Asp Gly Val Cys Thr Asp Ile Gly Gly Asp Phe
180 185 190
Arg Cys Arg Cys Pro Ala Gly Phe Ile Asp Lys Thr Cys Ser Arg Pro
195 200 205
Val Thr Asn Cys Ala Ser Ser Pro Cys Gln Asn Gly Gly Thr Cys Leu
210 215 220
Gln His Thr Gln Val Ser Tyr Glu Cys Leu Cys Lys Pro Glu Phe Thr
225 230 235 240
Gly Leu Thr Cys Val Lys Lys Arg Ala Leu Ser Pro Gln Gln Val Thr
245 250 255
Arg Leu Pro Ser Gly Tyr Gly Leu Ala Tyr Arg Leu Thr Pro Gly Val
260 265 270
His Glu Leu Pro Val Gln Gln Pro Glu His Arg Ile Leu Lys Val Ser
275 280 285
Met Lys Glu Leu Asn Lys Lys Thr Pro Leu Leu Thr Glu Gly Gln Ala
290 295 300
Ile Cys Phe Thr Ile Leu Gly Val Leu Thr Ser Leu Val Val Leu Gly
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Thr Val Gly Ile Val Phe Leu Asn Lys Cys Glu Thr Trp Val Ser Asn
325 330 335
Leu Arg Tyr Asn His Met Leu Arg Lys Lys Lys Asn Leu Leu Leu Gln
340 345 350
Tyr Asn Ser Gly Glu Asp Leu Ala Val Asn Ile Ile Phe Pro Glu Lys
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Ile Asp Met Thr Thr Phe Ser Lys Glu Ala Gly Asp Glu Glu Ile
370 375 380
Claims (9)
1. Application of urine protein delta homolog 1 and polypeptide fragments thereof in preparation of preparations for diagnosis and treatment of gestational diabetes patients, monitoring and evaluation of blood sugar and metabolic state, mechanism research and the like.
2. The use according to claim 1, wherein the amino acid sequence of urinary protein delta homolog 1 is set forth in SEQ ID No. 1; or an amino acid sequence which is derived from the amino acid sequence shown in SEQ ID NO.1 and has the same function with the amino acid sequence shown in SEQ ID NO. 1.
3. The use of claim 1, wherein the preparation is a kit for detecting urine protein delta homolog 1 and polypeptide fragments thereof from a gestational diabetic patient.
4. Use according to claim 3, wherein the kit comprises an immunization method for antigen-antibody reactions and kits thereof such as one or more of aptamer antibodies or antibody fragments capable of specifically binding protein delta homolog 1 and polypeptide fragments thereof.
5. The use of claim 3, wherein the kit comprises a method for direct detection of protein delta homolog 1 and polypeptide fragments thereof by mass spectrometry and related kits thereof.
6. The use of claim 3, wherein the kit comprises methods for directly detecting protein delta homolog 1 and polypeptide fragments thereof or nucleic acid related thereto and kits related thereto.
7. The use according to claim 3, wherein the kit further comprises a component selected from the group consisting of: the kit comprises a solid phase carrier, a diluent, a reference substance, a standard substance, a quality control substance, a detection antibody, a second antibody diluent, a luminescent reagent, a washing solution, a color development solution and a stop solution, wherein the solid phase carrier is any one or a combination of a plurality of the solid phase carrier, the diluent, the reference substance, the standard substance, the quality control substance, the detection antibody, the second antibody and the second antibody diluent.
8. The use of claim 7, wherein the standard comprises a protein delta homolog 1 standard, a humanized tag antibody standard; preferably, the quality control product comprises: quality control products of the protein delta congener 1 and humanized label antibody; preferably, the solid support comprises: particles, microspheres, glass slides, test strips, plastic beads, liquid phase chips, micro-porous plates or affinity membranes and other carriers with the same functions.
9. The use of claim 8, wherein the solid phase carrier is made of any one of polyvinyl chloride, polystyrene, polyacrylamide, cellulose, and carriers with similar functions.
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