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.

项目总结(见说明)： 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。 使这一观察复杂化的是，并不是所有BMI升高的人都会发展为动脉粥样硬化性血栓疾病。我们使用分离的血小板的RNA，通过高通量定量逆转录聚合酶链式反应，在超过2250名弗雷明翰后代和欧尼少数民族队列(FHS)的参与者中测量了48个基因的表达，发现特定的线粒体转录本与较高的体重指数显著和特异地相关。为了确定是否存在与血小板功能相关的变化，我们研究了短期甘油三酯乳剂输注(急性效应)后选择个体的血小板转录本和功能，发现血小板转录本中与 血小板被激活。因此，该项目的中心假设是：在肥胖的背景下，人类的血小板被重新编程，如改变的血小板RNA，包括线粒体转录本，这些变化导致血栓前表型，影响动脉粥样硬化性疾病的发展。肥胖对人类血小板转录谱和血小板功能的影响将研究如下 目的：1.研究BMI增加时血小板的分子特征，确定BMI增加是由短期脂肪摄入引起的还是由慢性肥胖引起的，这种变化是否随着体重减轻而可逆。目的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。目的3.确定血小板重编程是否与亚临床心血管疾病(CVD)和临床心血管疾病的发生有关。这些信息连同项目1-3的转录本和在AIM 1中筛选的蛋白质将建立一个生物标记物小组，识别体重指数升高的人患动脉粥样硬化性血栓疾病的高风险。该项目不仅试图确定血小板重新编程改变功能的机制，而且还将确定与人类的相关性，并开发基于文字记录的简档。