Reprogrammed Platelets: Effectors of Thrombosis in Metabolic Syndromes

重编程血小板：代谢综合征中血栓形成的效应器

基本信息

批准号：
8656415
负责人：
Andrew S Weyrich
金额：
$ 261.08万
依托单位：
UNIVERSITY OF UTAH
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：
2012-05-01 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8656415
关键词：
Acute Address Adhesions Basic Science Blood Blood Glucose Blood Platelets Blood Vessels Blood coagulation Cells Center for Translational Science Activities Clinical Clinical Investigator Clinical Research Clinical Trials Commit Comorbidity Diabetes Mellitus Disease Emulsions Enrollment Event Framingham Heart Study Genes Genetic Translation Glucose Glucose Transporter Hemostatic Agents Hemostatic function Human Hyperactive behavior Incidence Infection Inflammation Inflammatory Infusion procedures Laboratories Lipids Mammalian Cell Mediator of activation protein Megakaryocytes Megakaryocytopoieses Metabolic Metabolic Diseases Metabolic syndrome MicroRNAs Mitochondria Molecular Molecular Medicine Neoplasms Non-Insulin-Dependent Diabetes Mellitus Nonesterified Fatty Acids Nutritional Obesity Parents Patients Pattern Phase Phenotype Pleural Prevalence Proteins RNA Records Regulation Regulatory Pathway Research Research Infrastructure Research Personnel Research Project Grants Risk Role Sentinel Signal Transduction Stress Stroke Testing Therapeutic Thrombopoiesis Thrombosis Tissues Transcript Translational Research Triglycerides Universities Utah Vascular Diseases acute coronary syndrome atherothrombosis bariatric surgery career development diabetes management diabetic genetic manipulation insight insulin signaling novel pressure programs repaired response screening translational study

项目摘要

The broad objective of the University of Utah Molecular Medicine Translation Research Center in Thrombosis (U2M2-TRCT) is to dissect novel clinical and molecular determinants of thrombotic risk in patients with metabolic disorders (obesity, diabetes, and the metabolic syndrome). The U2M2-TRCT unites a group of basic and clinical investigators with breadth and expertise in thrombosis and metabolic dysregulation. Our studies will test the thematic hypothesis that metabolic changes in the systemic milieu reprogram platelet precursors and platelets themselves, resulting in altered thrombotic activities of these critical cells. To examin this central theme, we propose four research projects and four cores and studies by a cadre of established and emerging investigators with proven track records of productive interactions. The intellectual infrastructure is as follows: Project 1, The Molecular Regulation of Platelet Reprogramming by the Metabolic Milieu, characterizes reprogramming events in platelets and dissects the mechanisms by which microRNAs influence platelet phenotypes in metabolic syndromes; Project 2, Metabolic Regulation of Platelet Reprogramming, will determine how genetic manipulation of glucose transporters and modulators of mitochondrial function regulate reprogramming events and functional activities of platelets; Project 3, The Role of the Metabolic Milieu in Regulating Platelet Reprogramming in Humans, prospectively examines platelet reprogramming and platelet hyperreactivity imposed by the metabolic milieu of type 2 diabetes. Project 3 will also determine if therapeutic correction of metabolic imbalances reverses platelet reprogramming and hyperactivity; Project 4, Platelet Reprogramming in Human Obesity and Diabetes, will evaluate platelet reprogramming and function in subjects exposed to acute triglyceride emulsion infusion, obese subjects before and after bariatric surgery, and patients enrolled in the Framingham Heart Study. Screening of an early-phase translation mRNA nanochip in humans with metabolic syndromes is a key feature in Project 4. Together, our translational studies will explore new paradigms in thrombosis and metabolic syndromes, and will be a unique platform for research career development.

犹他大学血栓形成分子医学转化研究中心 (U2M2-TRCT) 的总体目标是剖析代谢性疾病（肥胖、糖尿病和代谢综合征）患者血栓风险的新临床和分子决定因素。 U2M2-TRCT 联合了一组在血栓形成和代谢失调方面具有广度和专业知识的基础和临床研究人员。我们的研究将检验以下主题假设：全身环境中的代谢变化会重新编程血小板前体和血小板本身，从而导致这些关键细胞的血栓形成活动发生改变。为了检验这一中心主题，我们提出了四个研究项目和四个核心研究，并由一批已建立和新兴的研究人员进行研究，这些研究人员具有有效的互动记录。智力基础设施如下：项目1，代谢环境对血小板重编程的分子调节，描述了血小板重编程事件的特征，并剖析了代谢综合征中microRNA影响血小板表型的机制；项目2，血小板重编程的代谢调节，将确定葡萄糖转运蛋白和线粒体功能调节剂的基因操作如何调节血小板重编程事件和功能活动；项目 3“代谢环境在调节人类血小板重编程中的作用”前瞻性地研究了 2 型糖尿病代谢环境造成的血小板重编程和血小板高反应性。项目 3 还将确定代谢失衡的治疗纠正是否可以逆转血小板重编程和过度活跃；项目 4，人类肥胖和糖尿病中的血小板重编程，将评估接受急性甘油三酯乳液输注的受试者、减肥手术前后的肥胖受试者以及参加弗雷明汉心脏研究的患者的血小板重编程和功能。在患有代谢综合征的人类中筛选早期翻译 mRNA 纳米芯片是项目 4 的一个关键特征。我们的转化研究将共同探索血栓形成和代谢综合征的新范例，并将成为研究职业发展的独特平台。