Platelet Reprogramming in Human Obesity and Diabetes

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。 使这一观察结果复杂化的是，并非所有BMI升高的个体都会发展为动脉粥样硬化血栓性疾病。我们使用来自分离血小板的RNA，通过高通量定量逆转录PCR测量了超过2250名Frachial Offspring和Omni minority cohort（FHS）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相关。为了确定血小板功能是否有相关的变化，我们研究了短期甘油三酯乳剂输注（急性效应）后个体的血小板转录物和功能，并确定了与血小板功能变化相关的血小板转录物的类似改变。 血小板活化因此，该项目的中心假设是：在肥胖症的背景下，人类血小板被重新编程，如通过改变的血小板RNA所看到的，包括线粒体转录物，并且这些变化导致影响动脉粥样硬化血栓形成疾病的发展的血栓形成前表型。将研究肥胖对人血小板的影响，如在其转录谱和血小板功能中所见， 目标1.在BMI增加的情况下表征血小板的分子特征，并确定其是否由短期脂肪摄入或慢性肥胖引起，以及这些变化是否随体重减轻而可逆。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。该信息沿着来自项目1-3的转录物和目标1中筛选的蛋白质将建立生物标志物组，其鉴定具有升高的BMI的个体处于动脉粥样硬化血栓性疾病的高风险。该项目不仅旨在确定血小板重编程改变功能的机制，而且还将确定人类相关性并开发基于转录的概况。

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.