Inflammation-mediated platelet hyperreactivity and thrombosis

炎症介导的血小板高反应性和血栓形成

基本信息

批准号：
10643806
负责人：
Pavel Davizon-Castillo
金额：
$ 21.07万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
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/10643806
关键词：
Adult Advisory Committees Aging Area Autophagocytosis Award Big Data Biochemical Biology Blood Platelets Cardiovascular Diseases Career Transition Award Caring Child Chronic Chronic Childhood Arthritis Coagulation Process Coronary Circulation Data Data Analyses Dedications 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 Outcome Pathway interactions Patients Pediatrics Pentosephosphate Pathway 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 career career development clinically relevant cost estimate experience high risk improved metabolome metabolomics mortality mouse model multidisciplinary novel novel therapeutic intervention older patient pharmacologic platelet function professor programs recruit skills skills training stem thrombotic tool transcriptomics

项目摘要

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.

项目概要/摘要候选人是儿科助理教授和年轻的医师科学家，致力于发展专注于研究炎症和炎症的交叉点的学术生涯通过研究炎症促进血小板形成的机制来形成血栓具有丰富的炎症、巨核细胞和血小板生物学背景，候选人希望发展自噬和新陈代谢方面的新专业知识，以确定他们的职业发展计划描述了对血小板高反应性和血栓形成的贡献。提案中概述了 2 年的指导培训，包括技术技能培训和职业培训发展活动，促进向独立的成功过渡和未来的资助。候选人的导师和联合导师拥有出色的翻译记录研究生产力和成功的指导：研究计划：炎症的贡献。促进心血管疾病（CVD）的发展并促进血小板高反应性和老年人（衰老）和类风湿性关节炎（RA）患者的血栓形成。这些群体经历的事件的特征是富含血小板的动脉血栓，这表明血小板高反应性是这些人群发病率和死亡率升高的主要原因。该申请的中心假设是慢性炎症促进血小板通过关键血小板代谢途径的重新编程来抑制高反应性和血栓形成。本申请中提出的工作旨在阐明慢性疾病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因子，例如自噬（目标 1）和磷酸戊糖途径（PPP，[目标 2]）在老年人和类风湿性关节炎患者中（目标 3）。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 博士）、代谢组学（Angelo D’Alessandro 博士）和血小板生物学（Matthew Rondina，医学博士）指导成功完成拟议的工作。在该奖项的 K99 阶段开发的指导、技能和工具将奠定为建立我的独立研究计划奠定了坚实的基础，专注于研究最后，也是最重要的，血小板代谢过度反应和血栓形成的决定因素。我们的研究发现不仅有可能改善护理和结果老年人和 RA 患者，以及患有慢性炎症的儿童，例如如幼年特发性关节炎 (JIA) 和镰状细胞病。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Extracellular Vesicle Size Reveals Cargo Specific to Coagulation and Inflammation in Pediatric and Adult Sickle Cell Disease.

DOI：
10.1177/10760296231186144
发表时间：
2023-01
期刊：
CLINICAL AND APPLIED THROMBOSIS-HEMOSTASIS
影响因子：
2.9
作者：
Thangaraju, Kiruphagaran;Setua, Saini;Lisk, Christina;Swindle, Delaney;Stephenson, Daniel;Dzieciatkowska, Monika;Lamb, Derek R.;Moitra, Parikshit;Pak, David;Hassell, Kathryn;George, Gemlyn;Nuss, Rachelle;Davizon-Castillo, Pavel;Stenmark, Kurt R.;D'Alessandro, Angelo;Irwin, David C.;Buehler, Paul W.
通讯作者：
Buehler, Paul W.

Platelets from blood diversion pouches (DPs) are a suitable alternative for functional, bioenergetic, and metabolomic analyses.

血液分流袋 (DP) 中的血小板是功能、生物能和代谢组学分析的合适替代品。

DOI：
10.2450/bloodtransfus.519
发表时间：
2023
期刊：
Blood transfusion = Trasfusione del sangue
影响因子：
0
作者：
Esparza,Orlando;Hernandez,Giovanny;Rojas-Sanchez,Guadalupe;Calzada-Martinez,Jorge;Nemkov,Travis;Kelher,Marguerite;Kelly,Kathleen;Silliman,ChristopherC;DomBourian,Melkon;Dumont,LarryJ;D'Alessandro,Angelo;Davizon-Castillo,Pavel
通讯作者：
Davizon-Castillo,Pavel

PU.1 Expression Defines Distinct Functional Activities in the Phenotypic HSC Compartment of a Murine Inflammatory Stress Model.

DOI：
10.3390/cells11040680
发表时间：
2022-02-15
期刊：
Cells
影响因子：
6
作者：
Chavez JS;Rabe JL;Hernandez G;Mills TS;Niño KE;Davizon-Castillo P;Pietras EM
通讯作者：
Pietras EM

Moderate hypoxia induces metabolic divergence in circulating monocytes and tissue resident macrophages from Berkeley sickle cell anemia mice.