Inflammation-mediated platelet hyperreactivity and thrombosis

炎症介导的血小板高反应性和血栓形成

• 批准号: 10117808
• 负责人: Pavel Davizon-Castillo
• 金额: $ 21.54万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-05 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10117808
• 关键词: Adult; Advisory Committees; Aging; Area; Autophagocytosis; Award; Big Data; Biochemical; Biology; Blood Platelets; Cardiovascular Diseases; Career Transition Award; Child; Chronic; Chronic Childhood Arthritis; Coagulation Process; Coronary Circulation; Data; Data Analyses; Development; Development Plans; Disease; Doctor of Philosophy; Elderly; Elements; Environment; Event; Flow Cytometry; Foundations; Functional disorder; Funding; Future; Goals; Human; Impairment; Incidence; Individual; Inflammation; Inflammatory; Investigation; Mediating; Megakaryocytes; Mentors; Mentorship; Metabolic; Metabolic Pathway; Metabolism; Microscopy; Mitochondria; Molecular; Morbidity - disease rate; Mus; Pathway interactions; Patients; Pediatrics; Pentosephosphate Pathway; Pharmacology; Phase; Physicians; Population; Populations at Risk; Productivity; Publishing; Records; Regulation; Research; Research Personnel; Rheumatoid Arthritis; Ribosomes; Role; Scientist; Sickle Cell Anemia; Solid; Stroke; TNF gene; Technical Expertise; Thrombosis; Thrombus; Training; Translational Research; Work; analytical method; atherothrombosis; care outcomes; career; career development; clinically relevant; cost estimate; experience; high risk; improved; individual patient; metabolome; metabolomics; mortality; mouse model; multidisciplinary; novel; novel therapeutic intervention; older patient; platelet function; professor; programs; recruit; skills; skills training; stem; thrombotic; tool; transcriptomics

Project Summary/Abstract The Candidate is an assistant professor in pediatrics and a young physician-scientist dedicated to developing an academic career focused on investigating the intersection of inflammation and thrombosis through the study of the mechanisms by which inflammation promotes platelet hyperreactivity. With a strong background in inflammation, megakaryocyte, and platelet biology, the candidate looks to develop new expertise in autophagy and metabolism to determine their contribution to platelet hyperreactivity and thrombosis. The Career Development Plan described in the proposal outlines 2 years of mentored training, including technical skill training and career development activities, to promote the successful transition to independence and future funding. The Candidate’s Mentors and Co-Mentors have proven track-records of excellent translational research productivity and successful mentorship. The Research Plan: Inflammation contributes to the development of cardiovascular disease (CVD) and promotes platelet hyperreactivity and thrombosis in older humans (aging) and patients with rheumatoid arthritis (RA). The thrombotic events experienced by these groups are characterized by platelet-rich arterial clots denoting that platelet hyperreactivity is central for the elevated morbidity and mortality in these populations. The central hypothesis of this application is that chronic inflammation promotes platelet hyperreactivity and thrombosis through the reprogramming of key platelet metabolic pathways. The work proposed in this application is set to elucidate the mechanisms by which chronic inflammation promotes platelet hyperreactivity through dysregulation of critical metabolic regulators of platelet function such as autophagy (aim 1) and the pentose phosphate pathway (PPP, [aim 2]) in older humans and in patients with rheumatoid arthritis (aim3). For this purpose, I have integrated multidisciplinary mentoring and advisory teams of world-known experts in autophagy (Andrew Thorburn, Ph.D.), metabolomics (Angelo D’Alessandro Ph.D.), and platelet biology (Matthew Rondina, MD) to guide the successful completion of the proposed work. The mentoring, skills, and tools developed throughout the K99 phase of this award will lay down a solid foundation to establish my independent research program focused on the study of the platelet metabolic determinants for hyperreactivity and thrombosis. Finally, and most important, discoveries from our research have the potential to improve the care and outcomes not only for older individuals and patients with RA but also children with chronic inflammatory conditions such as Juvenile Idiopathic Arthritis (JIA) and sickle cell disease.

项目总结/摘要 候选人是一位儿科助理教授，也是一位年轻的医生兼科学家， 发展学术生涯，专注于研究炎症和 通过研究炎症促进血小板生成的机制， 反应过度在炎症、巨核细胞和血小板生物学方面有很强的背景， 候选人希望在自噬和代谢方面发展新的专业知识，以确定他们的 导致血小板高反应性和血栓形成。职业发展计划描述 在建议书中概述了2年的指导培训，包括技术技能培训和职业生涯 发展活动，以促进成功过渡到独立和未来的资金。 候选人的导师和共同导师具有出色的翻译记录 研究生产力和成功的指导。研究计划：炎症有助于 导致心血管疾病（CVD）的发生并促进血小板高反应性， 在老年人（衰老）和类风湿性关节炎（RA）患者中，血栓性 这些群体经历的事件的特征是富含血小板的动脉凝块， 血小板高反应性是这些人群中发病率和死亡率升高的中心原因。 本申请的中心假设是慢性炎症促进血小板聚集， 高反应性和血栓形成通过重新编程的关键血小板代谢途径。 本申请中提出的工作旨在阐明慢性炎症的机制。 炎症通过关键代谢失调促进血小板高反应性 血小板功能的调节剂，如自噬（aim 1）和戊糖磷酸途径 (PPP，[aim 2]）在老年人和类风湿性关节炎患者中（aim 3）。为此目的， 我已经整合了多学科的指导和咨询团队的世界知名专家， 自噬（Andrew Thorburn，Ph.D.），代谢组学（Angelo D 'Alessandro博士），和血小板 生物学（马修Rondina，医学博士），以指导成功完成拟议的工作。的 在本奖项的K99阶段开发的指导、技能和工具将奠定 坚实的基础，建立我的独立研究计划，重点研究 高反应性和血栓形成的血小板代谢决定因素。最后，也是最重要的， 我们的研究发现有可能改善护理和结果， 老年人和RA患者，以及患有慢性炎症性疾病的儿童， 幼年特发性关节炎（JIA）和镰状细胞病。