Hyperglycemia, thromboxane and platelet activity in diabetes mellitus

糖尿病中的高血糖、血栓素和血小板活性

• 批准号: 8344530
• 负责人: JOHN HWA
• 金额: $ 41.51万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8344530
• 关键词: Acute; Aldehyde Reductase; Antiplatelet Drugs; Aspirin; Biochemical; Biochemical Genetics; Blood Cells; Blood Platelets; Blood Vessels; Cardiovascular Diseases; Cardiovascular system; Cell Culture System; Cessation of life; Chemotherapy-Oncologic Procedure; Chronic; Clinical; Clinical Trials; Collagen; Complement; Coronary artery; Coupled; Development; Diabetes Mellitus; Diabetic Angiopathies; Diabetic mouse; Disease; Exhibits; Functional disorder; Generations; Glucose; Goals; Heart failure; Hospitals; Human; Hyperactive behavior; Hyperglycemia; In Vitro; Mediating; Megakaryocytes; Metabolic; Methods; Molecular; Morbidity - disease rate; Mus; Non-Insulin-Dependent Diabetes Mellitus; Non-Steroidal Anti-Inflammatory Agents; Outcome; Pathogenesis; Pathway interactions; Patients; Platelet Activation; Play; Research; Role; Signal Pathway; Signal Transduction; Testing; Therapeutic; Thrombosis; Thromboxane Production; Thromboxanes; Transgenic Mice; United States; Variant; acute coronary syndrome; artery occlusion; base; cardiovascular risk factor; combat; computerized data processing; diabetic; diabetic patient; enzyme pathway; genetic variant; improved; in vivo; mortality; mouse model; non-diabetic; novel; particle; polyol; programs; receptor; response; tissue/cell culture

DESCRIPTION (provided by applicant): Diabetes mellitus is a major cause of cardiovascular morbidity and mortality in the United States. Enhanced platelet function participates in the pathogenesis of vascular complications. We have recently observed that there is significant thromboxane release from diabetic platelets particularly during hyperglycemia and that aldose reductase may play a significant role in promoting platelet hyperactivity. Our goals are to discover the mechanism by which hyperglycemia is transduced into thromboxane release contributing to diabetic platelet dysfunction. Through three Specific Aims we will initially addres the role of aldose reductase in transducing this high glucose signal to platelet dysfunction (Specific Aim #1). Specific Aim #2 will determine whether this signaling process may contribute to aspirin insensitivity that is often observed among diabetic patients, and Specific Aim #3 will assess how newly discovered genetic variants may influence both the response to hyperglycemia and aspirin insensitivity. At the conclusion of this research program we will have identified and confirmed a key metabolic and signaling component that transduces acute and chronic hyperglycemia into enhanced platelet activity. The results of these studies may support proceeding with clinical trials to determine what combination of antiplatelet agents would be most beneficial to protect against cardiovascular disease in diabetic patients. PUBLIC HEALTH RELEVANCE: Platelet hyperactivity in diabetic patients plays an important role in the development of cardiovascular disease. We will now explore the glucose specific mechanisms for this increase in thrombosis, by complementing human, mouse and tissue culture cell systems. Our proposed biochemical, genetic and signaling studies may assist in the development of new antiplatelet drugs for diabetic patients, in combating cardiovascular disease.

描述（由申请人提供）：糖尿病是美国心血管疾病发病和死亡的主要原因。血小板功能增强参与血管并发症的发病机制。我们最近观察到，糖尿病血小板中存在显着的血栓素释放，特别是在高血糖期间，并且醛糖还原酶可能在促进血小板过度活跃中发挥重要作用。我们的目标是发现高血糖转化为血栓素释放导致糖尿病血小板功能障碍的机制。通过三个具体目标，我们将首先阐述醛糖还原酶在将高葡萄糖信号转导至血小板功能障碍中的作用（具体目标#1）。具体目标#2将确定该信号传导过程是否可能导致糖尿病患者中经常观察到的阿司匹林不敏感，而具体目标#3将评估新发现的遗传变异如何影响对高血糖和阿司匹林不敏感的反应。在该研究计划结束时，我们将确定并确认一种关键的代谢和信号传导成分，该成分可将急性和慢性高血糖转化为增强的血小板活性。这些研究的结果可能支持进行临床试验，以确定哪种抗血小板药物组合最有利于预防糖尿病患者患心血管疾病。 公共卫生相关性：糖尿病患者的血小板过度活跃在心血管疾病的发展中起着重要作用。我们现在将通过补充人类、小鼠和组织培养细胞系统来探索血栓形成增加的葡萄糖特异性机制。我们提出的生化、遗传和信号传导研究可能有助于为糖尿病患者开发新的抗血小板药物，以对抗心血管疾病。