Platelet Reprogramming in Human Obesity and Diabetes

人类肥胖和糖尿病中的血小板重编程

基本信息

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
项目类别：
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

项目摘要

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（参见说明）：心血管疾病仍然是北美发病和死亡的主要原因。过早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。使这一观察变得复杂的是，并非所有体重指数升高的个体都会继续患上动脉粥样硬化血栓性疾病。我们使用分离血小板中的 RNA，通过高通量定量逆转录 PCR 测量了 Framingham Offspring 和 Omni 少数民族队列 (FHS) 2250 多名参与者中 48 个基因的表达，发现特定的线粒体转录物与较高的体重指数显着且特异性相关。为了确定血小板功能是否存在相关变化，我们研究了短期甘油三酯乳剂输注后个体的精选血小板转录本和功能（急性效应），并发现了与血小板功能变化相关的血小板转录本的类似变化。血小板活化。因此，该项目的中心假设是：在肥胖的情况下，通过改变血小板RNA（包括线粒体转录本）可以看出，人类血小板被重新编程，这些变化导致血栓形成表型，从而影响动脉粥样硬化血栓性疾病的发展。肥胖对人类血小板的影响（从其转录谱和血小板功能来看）将被研究为目标 1. 在 BMI 增加的情况下表征血小板的分子特征，并确定其是否是由短期脂肪摄入或慢性肥胖引起的，以及这些变化是否可以随着体重减轻而逆转。目标 2. 确定血小板重编程改变血小板功能（包括线粒体的作用）的机制。目标 3. 确定血小板重编程是否与亚临床心血管疾病 (CVD) 以及临床 CVD 的发展相关。这些信息与项目 1-3 的转录本以及目标 1 中筛选的蛋白质一起，将建立一个生物标志物组，识别 BMI 升高、动脉粥样硬化血栓性疾病高风险的个体。该项目不仅旨在定义血小板重编程改变功能的机制，还将确定人类相关性并开发基于转录的概况。