Human Studies on Blood Levels of Glycated CD59 as a Biomarker in Diabetes

描述(由申请人提供)：这项提案的目标是验证人类血液中的糖化CD59(GCD59)作为筛查试验来识别糖尿病前期患者，以及专注于糖尿病神经病变的糖尿病并发症的早期生物标志物。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)糖尿病并发症是美国发病率和死亡率的主要原因，以及3)治疗这些并发症的费用高达2450亿美元/年(预计到2034年将上升到3000亿美元)。糖化血红蛋白是治疗糖尿病患者的临床黄金标准，它不能识别出患某些并发症的高风险个体，也不够敏感，无法明确区分患有糖尿病前期的个体。慢性高血糖是人类糖尿病并发症的最终原因，但高血糖导致组织损伤的细胞和分子机制(S)仍然知之甚少。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，可以定量测定血液和组织中的GCD59。具体地说，我们已经证明：1)GCD59存在于糖尿病并发症的靶器官中，2)GCD59在正常血浆或血清中很容易被检测到。此外，我们的初步数据显示，GCD59在糖尿病患者或糖尿病前期患者以及妊娠糖尿病孕妇的血液中显著增加，b)是标准的2小时口服葡萄糖耐量试验确定的葡萄糖耐量的强大和独立的预测因子，以及c)似乎比HbA1c对个体内血糖负荷的变化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的所有必要工具和专业知识，包括针对GCD59的单抗和测定校准器，获得大量和多样化的糖尿病患者和非糖尿病患者，以及诊断工具。进行申请书中建议的所有研究所需的设备和专业知识。我们目标的成功实现将代表着在诊断、治疗和预防葡萄糖代谢紊乱和糖尿病的破坏性并发症方面取得的重大进展，并将有助于降低糖尿病及其并发症产生的极高成本。

DESCRIPTION (provided by applicant): The goal of this proposal is to validate glycated CD59 in human blood (GCD59) as a screening test to identify individuals with pre-diabetes, and an early bio-marker of diabetes complications focusing on diabetic neuropathy. This proposal is highly translational and addresses major Public Health priorities because 1) diabetes affects H 25 million Americans, 2) diabetes complications are a major cause of morbidity and mortality in the U.S., and 3) treatment of these complications costs a staggering 245 billion dollars/year (expected to rise to >300 billion by 2034). HbA1c, the clinical gold standard for management of patients with diabetes, does not identify individuals at higher risk of developing some complications and is not sensitive enough to clearly discriminate individuals with pre-diabetes. Chronic hyperglycemia is ultimately responsible for the complications of human diabetes but the cellular and molecular mechanism(s) by which hyperglycemia causes tissue damage are still poorly understood. 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 GCD59 in blood and tissues. Specifically, we have demonstrated that 1) GCD59 is present in target organs of diabetic complications, and 2) GCD59 can be readily measured in normal plasma or serum. Furthermore, our preliminary data show that GCD59 is a) significantly increased in the blood of individuals with diabetes or pre-diabetes as well as in pregnant women with gestational diabetes mellitus, b) is a strong and independent predictor of glucose tolerance determined by standard 2hr oral glucose tolerance test, and c) seems to respond faster than HbA1c to changes in glycemic load within an individual 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 large and diverse population of individuals with and without diabetes, and diagnostic tools, equipment and expertise necessary to conduct all studies proposed in the application. Successful accomplishment of our aims would represent a major advancement in diagnosis, treatment and prevention of the devastating complications of glucose dysmetabolism and diabetes, and should help lower the extremely high costs derived from diabetes and its complications.