Glycated CD59 as a novel biomarker of gestational diabetes mellitus

描述（由申请方提供）：本提案的目的是评估人血清中糖化CD 59作为筛查妊娠期糖尿病（GDM）的病理相关早期生物标志物。该提案具有高度转化性，并解决了主要的公共卫生优先事项，因为1）糖尿病影响2500万美国人，2）GDM是不良妊娠结局（包括巨大儿和先兆子痫）的主要来源。拟议的工作开辟了使用glyCD 59作为GDM生物标志物的可能性，这是对OGTT使用的创新偏离，OGTT是一种繁琐，昂贵和耗时的测试，重现性差，并且多次出现不必要的影响，包括恶心和呕吐。一种更简单，易于使用，患者友好的标记物，也参与了糖尿病及其并发症的发病机制，可能有助于满足广泛筛查GDM和预防相关不良后果的重要临床需求。申请人已经1）发现人CD 59通过糖化失活，2）提供了补体系统与糖尿病并发症的发病机制之间的联系的证据，和3）开发了允许定量人体液和组织中糖化的hCD 59的关键试剂。具体而言，我们已经证明1）糖化CD 59存在于糖尿病并发症的靶器官中，2）glyCD 59可以在正常尿液和血清中容易地测量。此外，我们的初步数据显示，glyCD 59 a）显著增加，（3-4倍），和B）似乎比HbA 1c更快地响应个体内血糖负荷的变化。在申请人和专家合作者的实验室中可获得实现我们的目标的所有必要工具和专业知识，包括糖化CD 59特异性单克隆抗体和测定校准品，接触在BWH接受产前护理的大量不同孕妇人群，以及进行申请中提议的所有研究所需的诊断工具、设备和专业知识。我们目标的成功实现将代表GDM筛查和早期诊断的重大进展。 公共卫生相关性：这一高度转化的提案a）旨在将血清糖化CD 59确定为GDM（GDM）的新型生物标志物，B）基于可靠的初步数据和所需的所有检测试剂/试剂的可用性，以及c）解决主要的公共卫生优先事项。这一目标的重要性突出表现在以下事实：1）GDM发生在所有妊娠的1 - 14%中，并且在美国正在上升，2）GDM是不良妊娠结局的主要原因，包括巨大儿、先兆子痫剖腹产、高胰岛素血症，3）不良结局可以通过适当的治疗来预防，4）在第24- 28周用OGTT筛查GDM现在是美国大多数寻求产前护理的孕妇的护理标准，5）口服葡萄糖耐量试验（OGTT），目前GDM筛查的金标准，繁琐，不舒服，有时会引起恶心和呕吐，并且不能完全重现。成功将允许使用一个更简单，更便宜，更病人友好和准确的筛查测试GDM。

DESCRIPTION (provided by applicant): The goal of this proposal is to assess glycated CD59 in human serum as a pathogenically relevant early bio-marker for screening of gestational diabetes mellitus (GDM). This proposal is highly translational and addresses major Public Health priorities because 1) diabetes affects H 25 million Americans, 2) and GDM is a major source of adverse pregnancy outcomes including macrosomia and pre-eclampsia. The proposed work opens the possibility of using glyCD59 as a biomarker for GDM, an innovative departure from the use of OGTT, a cumbersome, costly and time-consuming test with poor reproducibility and many times unwanted effects including nausea and vomiting. A simpler, easy to use, patient friendly marker that is also involved in the pathogenesis of diabetes and its complications may help fulfill an important clinical need in the widespread screening for GDM and prevention of associated adverse outcomes. 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 that allow quantification of glycated hCD59 in human fluids and tissues. Specifically, we have demonstrated that 1) glycated CD59 is present in target organs of diabetic complications, and 2) glyCD59 can be readily measured in normal urine and serum. Furthermore, our preliminary data show that glyCD59 is a) significantly increased (3-4 fold) in the serum of diabetic and pre-diabetics individuals, and b) seems to respond faster than HbA1c to changes in glycemic load within an individual All necessary tools and expertise to accomplish our aim are available in the laboratory of the applicant and expert collaborators, including monoclonal antibodies specific for glycated CD59 and assay calibrators, access to large and diverse population of pregnant women undergoing pre-natal care at BWH, and diagnostic tools, equipment and expertise to necessary to conduct all studies proposed in the application. Successful accomplishment of our aims would represent a major advancement in screening and early diagnosis of GDM. PUBLIC HEALTH RELEVANCE: This highly translational proposal a) aims at establishing serum glycated CD59 as a novel biomarker of Gestational Diabetes Mellitus (GDM), b) is based on robust preliminary data and availability of all assays/reagents needed, and c) addresses major Public Health priorities. The importance of this goal is highlighted by the fact that 1) GDM occurs in 1 to 14% of all pregnancies, and is rising in the United States, 2) GDM is a major cause of adverse pregnancy outcomes including macrosomia, pre-eclampsia C-sections, hyperinsulinemia, 3) adverse outcomes can be prevented with adequate treatment, 4) screening for GDM with OGTT at 24-28th weeks is now the standard of care for most pregnant women seeking prenatal care in the United States, and 5) oral glucose tolerance test (OGTT), the current gold standard for GDM screening, is cumbersome, uncomfortable, at times causes nausea and vomiting and is not fully reproducible. Success will allow the use of a simpler, cheaper, more patient-friendly and accurate screening test for GDM.