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: 10364761
• 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/10364761
• 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.

项目摘要/摘要 这位候选人是一位儿科学助理教授，也是一位致力于 致力于研究炎症与疾病的交集 通过研究炎症促进血小板的机制而形成血栓 高反应性。在炎症、巨核细胞和血小板生物学方面有很强的背景， 候选人希望开发自噬和新陈代谢方面的新专业知识，以确定他们的 对血小板高反应性和血栓形成的贡献。所描述的职业发展计划 在建议书中列出了两年的指导性培训，包括技术技能培训和职业生涯 发展活动，以促进向独立和未来供资的成功过渡。 候选人的导师和联合导师都有出色的翻译记录 研究效率和成功的导师。研究计划：炎症起作用 与心血管疾病(CVD)的发展有关，并促进血小板的高反应性和 老年人(老龄化)和类风湿性关节炎(RA)患者的血栓形成。血栓形成 这些人群经历的事件以富含血小板的动脉血栓为特征，这表明 在这些人群中，血小板高反应性是发病率和死亡率升高的主要原因。 这一应用的中心假设是慢性炎症促进了血小板 通过对关键的血小板代谢途径重新编程而导致的高反应性和血栓形成。 本申请中提出的工作旨在阐明慢性阻塞性肺疾病 炎症通过关键代谢紊乱促进血小板高反应性 血小板功能的调节，如自噬(Aim 1)和磷酸戊糖途径 (购买力平价，[目标2])在老年人和类风湿性关节炎患者中(目标3)。为此， 我整合了由世界知名专家组成的多学科指导和咨询团队， 自噬(Andrew Thorburn，Ph.D.)、代谢组学(Angelo D‘Alessandro Ph.D.)和血小板 生物学(Matthew Rondina，MD)，以指导拟议工作的成功完成。这个 在该奖项的K99阶段开发的指导、技能和工具将为 扎实的基础建立了我的独立研究计划，重点研究了 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， 我们的研究发现不仅有可能改善患者的护理和预后 老年人和RA患者以及患有慢性炎症性疾病的儿童，如 如青少年特发性关节炎(JIA)和镰状细胞病。