Blood Levels of Glycated CD59, a Novel Biomarker to Assess Pregnancy-induced Glucose Intolerance

糖化 CD59 的血液水平，一种评估妊娠引起的葡萄糖不耐受的新型生物标志物

• 批准号: 10599099
• 负责人: JOSE A HALPERIN
• 金额: $ 69.78万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10599099
• 关键词: Address; Admission activity; Affect; Agreement; Aneuploidy; Biological Assay; Biological Markers; Birth trauma; Blood; Blood specimen; Cardiovascular Diseases; Caring; Categories; Cell membrane; Cesarean section; Classification; Clinical; Complement; Complications of Diabetes Mellitus; Consumption; Cross-Sectional Studies; Data; Diabetes Mellitus; Diagnosis; Diagnostic tests; Dystocia; Early Diagnosis; Early Intervention; Enzyme-Linked Immunosorbent Assay; Epidemic; Equipment; Fetal Growth Retardation; Fetus; Frequencies; Fructosamine; Funding; Future; Gene Expression; Gestational Age; Gestational Diabetes; Glucose; Glucose Intolerance; Glycosylated hemoglobin A; Goals; Grant; Guidelines; Human; Hyperglycemia; Hyperinsulinism; Incidence; Individual; Infant; Insulin; International; Intervention; Laboratories; Link; Measurement; Measures; Metabolic; Methods; Modeling; Molecular; Monoclonal Antibodies; Mothers; Neonatal Hypoglycemia; Newborn Infant; OGTT; Obesity; Oral; Outcome; Pathogenesis; Pharmaceutical Preparations; Pilot Projects; Plasma; Population Heterogeneity; Pre-Eclampsia; Pregnancy; Pregnant Women; Prenatal care; Prevalence; Prospective Studies; Public Health; Publications; Publishing; Reagent; Recommendation; Reproducibility; Research; Resources; Risk; Sampling; Second Pregnancy Trimester; Seminal; Sensitivity and Specificity; Shoulder; Testing; Therapeutic Intervention; Time; United States National Institutes of Health; United States Preventative Services Task Force; Validation; Visit; Woman; adverse outcome; adverse pregnancy outcome; clinical practice; cohort; complement system; cost effective; diagnosis standard; diagnostic tool; early detection biomarkers; early pregnancy; early screening; epidemiology study; fetal; gene function; genetic regulatory protein; glycation; imprint; malformation; maternal hyperglycemia; maternal outcome; non-diabetic; novel marker; perinatal complications; perinatal outcomes; public health priorities; rate of change; screening; standard of care; tool

Project Summary/Abstract – The goal of this proposal is to validate glycated CD59 (GCD59) in human blood as a novel biomarker to screen for studies of pregnancy-induced glucose intolerance. This proposal is highly translational and addresses major Public Health priorities because: 1) women with pregnancy-induced glucose intolerance and their fetus are at an increased risk of adverse clinical outcomes and perinatal complications, 2) the frequency of pregnancy-induced glucose intolerance is increasing at alarming rates, 3) epidemiological studies have shown that appropriate treatment reduces the associated risks for the mother and newborn, and 4) the glucose load tests, currently the gold standard identifying pregnancy-induced glucose intolerance, are expensive, time consuming, non-physiologic and unpleasant, have poor reproducibility on repeat testing. These facts highlight why there is agreement that a simpler, shorter, easier-to-use, cost-effective, sensitive and specific test would be a much better tool to screen for pregnancy-induced glucose intolerance. The applicants have 1) discovered that human CD59 is inactivated by glycation, 2) provided evidence for a link between the complement system and the pathogenesis of the complications of diabetes, and 3) developed key reagents and established a specific and sensitive assay that allows quantification of GCD59 in blood. With this assay, we have conducted pilot studies in pregnant women undergoing glucose- loading tests to screen for GDM. The results showed that a single measurement of plasma GCD59 at week ≈ 24-26 predicted pregnancy-induced glucose intolerance and GDM with high specificity and sensitivity (ROC AUC: 0.93). Based on these robust preliminary data and available resources, we now propose the highly focused aim of prospectively studying a large cohort of pregnant women to assess the utility of GCD59 as a simple, easy-to-use test for early prediction of pregnancy-induced glucose intolerance. All necessary tools and expertise to accomplish our aims are available in the laboratory of the applicant and expert collaborators, including monoclonal antibodies specific for GCD59 and assay calibrators, access to plasma samples from a large and diverse population of pregnant women undergoing standard of care screening for GDM, diagnostic tools, equipment and expertise necessary to conduct all studies proposed in the application. Successful accomplishment of our aim will provide a clinically useful and independent predictor to investigate pregnancy-induced glucose intolerance that could simplify the earlier screening and diagnosis of this condition.

项目总结/摘要 – 该提案的目标是验证人类血液中的糖化 CD59 (GCD59) 作为一种新型生物标志物 筛查妊娠引起的葡萄糖不耐症的研究该提案具有高度转化性和实用性。 解决主要公共卫生优先事项，因为：1) 患有妊娠引起的葡萄糖不耐受的妇女 及其胎儿出现不良临床结果和围产期并发症的风险增加，2) 妊娠引起的葡萄糖不耐受的频率正在以惊人的速度增加，3）流行病学研究 已经表明，适当的治疗可以降低母亲和新生儿的相关风险，并且 4) 葡萄糖负荷测试是目前识别妊娠引起的葡萄糖不耐受的金标准， 昂贵、耗时、非生理性且令人不快，重复测试的再现性差。 这些事实凸显了为什么人们一致认为更简单、更短、更易于使用、具有成本效益、敏感和 特定测试将是筛查妊娠引起的葡萄糖不耐受的更好工具。 申请人 1) 发现人类 CD59 通过糖化作用失活，2) 提供了证据 补体系统与糖尿病并发症发病机制之间的联系，3) 开发了关键试剂并建立了一种特异性且灵敏的检测方法，可以定量 GCD59 通过这种检测，我们对接受葡萄糖检测的孕妇进行了初步研究。 筛查 GDM 的负荷试验结果表明，单次测量血浆 GCD59 周 ≈ 。 24-26预测妊娠引起的葡萄糖不耐受和GDM具有高特异性和敏感性（ROC AUC：0.93）。基于这些可靠的初步数据和可用资源，我们现在提出高度的建议。 前瞻性研究一大群孕妇的重点目标是评估 GCD59 作为一种药物的效用 简单易用的测试，用于早期预测妊娠引起的葡萄糖耐受不良。 申请人的实验室可以提供实现我们目标所需的所有必要工具和专业知识，并且 专家合作者，包括 GCD59 特异性单克隆抗体和测定校准品，可获取 来自接受标准护理的大量不同孕妇的血浆样本 筛选进行所有拟议研究所需的 GDM、诊断工具、设备和专业知识 在应用程序中。 我们目标的成功实现将为临床提供一个有用且独立的预测因子 研究妊娠引起的葡萄糖不耐受，可以简化早期筛查和诊断 这个条件。

项目成果

Emerging Protein Biomarkers for the Diagnosis or Prediction of Gestational Diabetes-A Scoping Review.

• DOI: 10.3390/jcm10071533
• 发表时间: 2021-04-06
• 期刊: Journal of clinical medicine
• 影响因子: 3.9
• 作者: Bogdanet D;Reddin C;Murphy D;Doheny HC;Halperin JA;Dunne F;O'Shea PM
• 通讯作者: O'Shea PM

The Diagnostic Accuracy of Second Trimester Plasma Glycated CD59 (pGCD59) to Identify Women with Gestational Diabetes Mellitus Based on the 75 g OGTT Using the WHO Criteria: A Prospective Study of Non-Diabetic Pregnant Women in Ireland.

• DOI: 10.3390/jcm11133895
• 发表时间: 2022-07-04
• 期刊: Journal of clinical medicine
• 影响因子: 3.9

Plasma-glycated CD59 as an early biomarker for gestational diabetes mellitus: prospective cohort study protocol.

• DOI: 10.1136/bmjopen-2021-054773
• 发表时间: 2022-04-20
• 期刊: BMJ OPEN
• 影响因子: 2.9
• 作者: Andrews, Chloe;Toth-Castillo, Michelle;Aktas, Huseyin;Fernandez, Miguel-Angel Luque;Wong, Steven Koon;Sen, Sarbattama;Halperin, Jose
• 通讯作者: Halperin, Jose