Platelet Reprogramming in Human Obesity and Diabetes

人类肥胖和糖尿病中的血小板重编程

• 批准号: 8464247
• 负责人: Andrew S Weyrich
• 金额: $ 62.26万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8464247
• 关键词: Acute; Adipocytes; Biological Markers; Blood; Blood Clot; Blood Platelets; Blood coagulation; Body Weight decreased; Body mass index; Cardiovascular Diseases; Cardiovascular system; Cells; Chronic; Clinical; Clinical Research; Data; Development; Diabetes Mellitus; Dietary intake; Disease; Emulsions; Event; Fatty acid glycerol esters; Gene Expression; Genes; Glucose; Human; Incidence Study; Individual; Inflammatory; Infusion procedures; Instruction; Intake; Lead; Link; Lipids; Longitudinal Studies; Measurement; Measures; Mediator of activation protein; Metabolic; Metabolic syndrome; Methodology; MicroRNAs; Minority; Mitochondria; Molecular; Molecular Profiling; Morbidity - disease rate; Myocardial Ischemia; Non-Insulin-Dependent Diabetes Mellitus; North America; Obesity; Participant; Patient Education; Patients; Phenotype; Plasma; Platelet Activation; Population; Production; Proteins; RNA; Regression Analysis; Reverse Transcription; Risk; Risk Factors; Role; Thrombosis; Tissues; Transcript; Triglycerides; Weight; bariatric surgery; base; cardiovascular risk factor; clinically relevant; cohort; coronary artery calcification; cytokine; diabetes management; diabetic patient; high risk; inhibitor/antagonist; insight; mRNA Expression; mortality; novel; offspring; pre-clinical; premature atherosclerosis

PROJECT SUMMARY (See instructions): Cardiovascular disease continues to be the primary cause of morbidity and mortality in North America. The risk of premature atherosclerosis and platelet-dependent cardiovascular events rises with increasing obesity. Complicating this observation is that not all individuals with elevated BMI go on to develop athero-thrombotic disease. We measured expression of 48 genes by high-throughput quantitative reverse transcription PCR in over 2250 participants of the Framingham Offspring and Omni minority cohorts (FHS) using RNA from isolated platelets and found that specific mitochondrial transcripts were significantly and specifically associated with higher body mass index. To determine if there were associated changes in platelet function, we studied select platelet transcripts and function from individuals after short term triglyceride emulsion infusion (acute effect) and identified similar alterations in platelet transcripts that associated with changes in platelet activation. Thus, the central hypothesis of this project is: In the setting of obesity, the human platelet is reprogrammed as seen by altered platelet RNA, including mitochondrial transcripts, and these changes lead to a prothrombotic phenotype that influences the development of athero-thrombotic disease. The effect of obesity on the human platelet as seen in its transcript profile and platelet function will be studied as follows: Aim 1. Characterize the molecular signature of platelets in the setting of increased BMI and determine if it is caused by short term fat intake or chronic obesity and if the changes are reversible with weight loss. Aim 2. Determine the mechanism by which platelet reprogramming alters platelet function including the role of the mitochondria. Aim 3. Determine if platelet reprogramming correlates with subclinical cardiovascular disease (CVD) and the development of clinical CVD. This information along with transcripts from Projects 1-3 and proteins screened in Aim 1 will establish a biomarker panel identifying individuals with elevated BMI at high risk for athero-thrombotic disease. This project seeks not only to define the mechanism by which platelet reprogramming alters function but will determine the human relevance and develop a transcript-based profile.

项目摘要（请参阅说明）： 心血管疾病仍然是北美发病率和死亡率的主要原因。过早的动脉粥样硬化和血小板依赖性心血管事件的风险随着肥胖的增加而增加。 使这一观察结果复杂化的是，并非所有患有BMI升高的人都会出现动脉粥样硬化疾病。我们使用来自分离的血小板的RNA在2250多名弗雷明汉后代和omni少数族裔同龄人（FHS）中，通过高通量定量逆转录PCR测量了48个基因的表达，并发现特定的线粒体转录本具有显着性，并且与更高的体外质量指数显着相关。为了确定血小板功能是否存在相关的变化，我们研究了短期甘油三酸酯乳液输注（急性效应）之后的精选血小板转录本和功能 血小板激活。因此，该项目的中心假设是：在肥胖的情况下，人血小板被重编程，如改变的血小板RNA所示，包括线粒体转录本，这些变化会导致促血肿的表型，从而影响动脉粥样硬化疾病的发展。肥胖对人血小板的影响，如其转录本轮廓和血小板功能所示，将被研究为 以下内容：AIM 1。在增加BMI的情况下表征血小板的分子特征，并确定它是否是由短期脂肪摄入或慢性肥胖引起的，以及是否因体重减轻而可逆。目标2。确定血小板重编程改变血小板功能的机制，包括线粒体的作用。目标3。确定血小板重编程是否与亚临床心血管疾病（CVD）和临床CVD的发展相关。这些信息以及来自项目1-3的成绩单和在AIM 1中筛选的蛋白质将建立一个生物标记面板，该小组识别患有动脉粥样硬化疾病高风险的BMI升高的个体。该项目不仅旨在定义血小板重编程来改变功能的机制，而且还将决定人类的相关性并开发基于转录本的概况。