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

项目概要/摘要- 该提案的目标是验证人血液中的糖化CD 59（GCD 59）作为一种新的生物标志物， 筛查妊娠诱导的葡萄糖耐受不良的研究。该提案具有高度的翻译性， 解决了主要的公共卫生优先事项，因为：1）妊娠引起的葡萄糖耐受不良的妇女 和他们的胎儿在不良临床结果和围产期并发症的风险增加，2） 妊娠引起的葡萄糖耐受不良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，以及4） 葡萄糖负荷试验，目前的金标准，确定妊娠诱导的葡萄糖耐受不良， 昂贵、耗时、非生理性和令人不快，在重复测试中具有差的再现性。 这些事实突出说明了为什么人们一致认为，一种更简单、更短、更易于使用、成本效益高、敏感和 特异性测试将是筛查妊娠诱导葡萄糖耐受不良更好的工具。 申请人已经1）发现人CD 59通过糖化失活，2）提供了糖基化的证据， 补体系统与糖尿病并发症发病机制之间的联系，以及3） 开发了关键试剂，并建立了特异性和灵敏度的检测方法，可以定量GCD 59 是血通过这种检测，我们在接受葡萄糖-胰岛素联合治疗的孕妇中进行了初步研究。 进行妊娠期糖尿病筛查结果表明，在第12周时，单次测量血浆GCD 59 24-26预测妊娠葡萄糖耐受不良和GDM具有较高的特异性和敏感性（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 前瞻性研究一个大型孕妇队列，以评估GCD 59作为 一种简单易用的测试，用于早期预测妊娠引起的葡萄糖耐受不良。 所有必要的工具和专业知识，以实现我们的目标，可在实验室的申请人， 专家合作者，包括GCD 59特异性单克隆抗体和测定校准品， 来自接受标准护理的大量不同孕妇人群的血浆样本 GDM筛查、诊断工具、设备和进行所有拟议研究所需的专业知识 在应用程序中。 成功实现我们的目标将提供一个临床有用的和独立的预测， 研究妊娠引起的葡萄糖耐受不良，可以简化早期筛查和诊断， 这个条件。

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.