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

糖化 CD59 血液水平作为糖尿病生物标志物的人体研究

基本信息

批准号：
8668411
负责人：
JOSE A HALPERIN
金额：
$ 70.97万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8668411
关键词：
Achievement Active Sites Address Adult Affect American Amino Acids Atherosclerosis Biological Assay Biological Markers Biology Biometry Biopsy Blindness Blood Blood Vessels Cardiovascular Diseases Cell Proliferation Cell membrane Chronic Clinical Clinical Data Complement Complement Activation Complement Membrane Attack Complex Complications of Diabetes Mellitus Cross-Sectional Studies Data Development Diabetes Mellitus Diabetic Angiopathies Diabetic Neuropathies Diagnosis Diagnostic Distal End stage renal failure Enzyme-Linked Immunosorbent Assay Equilibrium Equipment Fiber Figs - dietary Foot Pain Funding Gestational Diabetes Glucose Glycosylated hemoglobin A Goals Gold Human Hyperglycemia Individual Inflammation Injection of therapeutic agent Insulin Kidney Diseases Kidney Transplantation Laboratories Laboratory Diagnosis Link Longitudinal Studies Measures Mediating Membrane Proteins Methods Molecular Monitor Monoclonal Antibodies Morbidity - disease rate Myocardial Infarction Nerve Neurologic Examination OGTT Organ Pain Pathogenesis Patients Peripheral Plasma Polyneuropathy Population Heterogeneity Prediabetes syndrome Pregnant Women Prevention Publishing Reagent Recording of previous events Reporting Research Research Personnel Retinal Diseases Risk Sensory Serum Site Skin Streptozocin Stroke Test Result Testing Thrombosis Time Tissues United States National Institutes of Health Validation Work base cohort complement system cost diabetic experience genetic regulatory protein glucose tolerance glycation high risk impaired glucose tolerance limb amputation mortality novel public health priorities public health relevance response screening tool

项目摘要

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.

描述（由申请人提供）：该提案的目标是验证人血液中的糖化 CD59（GCD59）作为筛查测试来识别糖尿病前期个体，以及糖尿病并发症的早期生物标志物，重点关注糖尿病神经病变。该提案具有高度转化性，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和死亡的主要原因，3) 这些并发症的治疗费用高达 2450 亿美元/年（预计到 2034 年将增至超过 3000 亿）。 HbA1c 是糖尿病患者管理的临床金标准，它不能识别出现某些并发症的较高风险的个体，并且不够敏感，无法清楚地区分糖尿病前期个体。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仍知之甚少。申请人 1) 发现人类 CD59 通过糖化失活，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) 开发了能够定量血液和组织中 GCD59 的关键试剂。具体来说，我们已经证明：1) GCD59 存在于糖尿病并发症的靶器官中，2) GCD59 可以在正常血浆或血清中轻松测量。此外，我们的初步数据表明，GCD59 a) 在患有糖尿病或糖尿病前期的个体以及患有妊娠期糖尿病的孕妇的血液中显着增加，b) 是通过标准 2 小时确定的葡萄糖耐量的强大且独立的预测因子口服葡萄糖耐量试验，以及 c) 似乎对个体血糖负荷变化的反应比 HbA1c 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GCD59 特异性单克隆抗体和检测校准品，接触大量不同人群的糖尿病患者和非糖尿病患者，以及进行申请中提出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着在诊断、治疗和预防葡萄糖代谢异常和糖尿病的破坏性并发症方面取得的重大进步，并应有助于降低糖尿病及其并发症带来的极高成本。