Glycated CD59 as a novel biomarker of gestational diabetes mellitus

描述(由申请人提供)：本提案的目标是评估人类血清中糖化的CD59作为妊娠期糖尿病(GDM)筛查的早期生物标志物的病原学意义。这项建议具有很高的翻译性，并解决了主要的公共卫生优先事项，因为1)糖尿病影响着2500万美国人，2)妊娠期糖尿病是不良妊娠结局的主要来源，包括巨大儿和先兆子痫。这项拟议的工作开启了将glCD59用作GDM生物标记物的可能性，这是对OGTT使用的一种创新，OGTT是一种繁琐、昂贵和耗时的测试，重复性差，而且多次出现恶心和呕吐等不良反应。一种更简单、易于使用、患者友好的标记物也参与糖尿病及其并发症的发病机制，可能有助于满足广泛筛查妊娠期糖尿病和预防相关不良后果的重要临床需求。申请者1)发现人类CD59被糖基化灭活，2)提供了补体系统与糖尿病并发症发病机制之间联系的证据，3)开发了关键试剂，可以定量测定人体体液和组织中糖基化的hCD59。具体地说，我们已经证明1)糖化的CD59存在于糖尿病并发症的靶器官中，2)在正常的尿液和血清中可以很容易地检测到糖化的CD59。此外，我们的初步数据显示，糖化CD59在糖尿病和糖尿病前期患者的血清中显著增加(3-4倍)，并且b)对个体内血糖负荷的变化似乎比HbA1c反应更快。申请人和专家合作者的实验室中提供了实现我们目标所需的所有必要工具和专业知识，包括针对糖化CD59的单抗和检测校准器，能够接触到在BWH接受产前护理的大量且多样化的孕妇，以及进行申请中建议的所有研究所需的诊断工具、设备和专业知识。成功实现我们的目标将代表着妊娠期糖尿病筛查和早期诊断方面的重大进步。

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.