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

基本信息

批准号：
8895384
负责人：
JOHN HWA
金额：
$ 41万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-01 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8895384
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 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 base cardiovascular risk factor combat coronary artery occlusion diabetic diabetic patient enzyme pathway genetic variant improved in vivo mortality mouse model non-diabetic novel particle polyol programs receptor response signal processing targeted treatment tissue/cell culture

项目摘要

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.

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。