Role of Hematopoietic System and Proteomics in HIV-Associated Cardiovascular Disease

造血系统和蛋白质组学在 HIV 相关心血管疾病中的作用

基本信息

批准号：
10393577
负责人：
Priscilla Y. Hsue
金额：
$ 19.35万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-03-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10393577
关键词：
Anti-Inflammatory Agents Atherosclerosis Award Basic Science Biological Blood Cells Blood Vessels Bone Marrow Cardiac Cardiology Cardiovascular Diseases Chronic Clinic Clinical Clinical Data Clinical Research Clinical Trials Coronary heart disease Data Development Disease Event Extramedullary Face Foundations Funding General Population Goals Grant HIV HIV Infections Heart failure Hematopoiesis Hematopoietic System Hematopoietic stem cells Image Individual Inflammation Inflammatory Infrastructure Interleukin-1 beta Intervention Investigation Kidney Diseases Laboratories Leadership Link Lipids Malignant Neoplasms Mentors Meta-Analysis Metabolic Monoclonal Antibodies Mutation PET/CT scan Pathogenesis Pathway interactions Persons Play Prevalence Process Proteins Proteomics Publications Pulmonary Hypertension Reporting Research Research Personnel Resources Risk Risk Factors Role Sampling San Francisco Science Site Somatic Mutation Technology Time Training Translational Research United States National Institutes of Health Visit Work aged aptamer base burden of illness cardiovascular disorder risk career career development clinical center clinical predictors comorbidity disability-adjusted life years fluorodeoxyglucose positron emission tomography follow-up hematopoietic tissue immune activation inflammatory marker inhibitor lymph nodes mortality multidisciplinary novel patient oriented patient oriented research prevent protein biomarkers proteomic signature stem cells translational research program translational study

项目摘要

Project Summary/Abstract Dr. Hsue is one of the few cardiologists in the world with both extensive research and clinical expertise in HIV and has devoted the last 15 years studying cardiovascular disease (CVD) in the setting of HIV. The initial part of her career was spent 1) establishing a HIV Cardiology Clinic at Zuckerberg San Francisco General (ZSFG), 2) developing the infrastructure to perform patient oriented research in Cardiology including development of a vascular laboratory for clinical research, 3) performing studies that evaluate the mechanisms underlying HIV infection and CVD and 4); leading clinical trials aimed to reducing inflammation and CVD risk in HIV. The findings from her work have shown that 1) HIV infection is independently associated with CVD, independent of traditional risk factors or ART and 2) chronic inflammation in the setting of effectively treated HIV infection underlies this increased CV risk. Initial K24 support has led to a significant increase in the number of mentees, grants, and publications for Dr. Hsue and new research directions including use of novel imaging to assess HIV disease burden and identification of therapies to reduce HIV-associated inflammation and CV risk. For the K24 renewal period, her career goals are to perform cutting edge clinical/translational studies and mentoring that will lead to improvements in treating, identifying and preventing CVD among PLWH and also impact other comorbidities and HIV cure. Dr. Hsue plans to 1) expand her research to include the role of somatic mutations in the hematopoietic system (termed clonal hematopoiesis of indeterminate potential, CHIP) and proteomics in HIV-associated CVD; 2) continue her time spent mentoring junior investigators in the fields of HIV infection, inflammation, and CVD with a focus on transition to full-independence; 3) obtain leadership training to build clinical and translational research programs that can be used by mentees and will make her a better mentor. The majority of Dr. Hsue's career development will occur at UCSF which offers outstanding resources for clinical/translational research, basic science, imaging, HIV, and mentoring/leadership training. Her K24 proposal will extend upon her current NIH-funded investigations by studying the underlying mechanism of HIV- associated atherosclerosis in treated HIV with the following Specific Aims: Aim 1A: To determine if clonal hematopoiesis of indeterminate potential (CHIP) mutations are more prevalent in peripheral blood cells of PLWH vs. uninfected controls; Aim 1B: To determine whether the presence of CHIP mutations are associated with increased arterial inflammation and metabolic activity of the hematopoietic system as assessed by FDG- PET/CT; Aim 2A: To identify a unique proteomic signature in PLWH that is associated with arterial inflammation and metabolic activity of the hematopoietic system, and Aim 2B: to characterize changes in proteins and biological pathways that are altered after anti-inflammatory and lipid interventions. This proposal will provide subject visits, imaging, and clinical and laboratory data to support new investigators in clinical/ translational research in the field of HIV-related CVD and HIV disease pathogenesis including cure.

项目概要/摘要徐医生是世界上为数不多的在艾滋病毒方面拥有广泛研究和临床专业知识的心脏病专家之一过去 15 年致力于研究 HIV 背景下的心血管疾病 (CVD)。初始部分她职业生涯的大部分时间花在了 1) 在扎克伯格旧金山总医院 (ZSFG) 建立了艾滋病毒心脏病诊所， 2) 开发基础设施以开展以患者为导向的心脏病学研究，包括开发用于临床研究的血管实验室，3) 进行评估 HIV 潜在机制的研究感染和 CVD 以及 4);旨在减少艾滋病毒炎症和心血管疾病风险的领先临床试验。这她的研究结果表明 1) HIV 感染与 CVD 独立相关，独立于传统危险因素或 ART 和 2) 有效治疗 HIV 感染时的慢性炎症是心血管风险增加的原因。最初的 K24 支持导致学员数量大幅增加，徐博士的资助和出版物以及新的研究方向，包括使用新颖的成像来评估 HIV 疾病负担和确定减少 HIV 相关炎症和心血管风险的疗法。对于 K24续约期，她的职业目标是进行前沿的临床/转化研究和指导这将改善 PLWH 中 CVD 的治疗、识别和预防，并影响其他方面合并症和艾滋病毒治疗。 Hsue 博士计划 1) 扩大她的研究范围，将体细胞突变的作用纳入其中造血系统（称为不确定潜力克隆造血，CHIP）和蛋白质组学 HIV相关CVD； 2) 继续花时间指导艾滋病毒感染领域的初级研究人员，炎症和心血管疾病，重点是向完全独立的过渡； 3）获得领导力建设培训可供学员使用的临床和转化研究项目，将使她成为更好的导师。徐博士的大部分职业发展将在加州大学旧金山分校进行，该校为以下领域提供了优秀的资源：临床/转化研究、基础科学、成像、艾滋病毒和指导/领导力培训。她的K24 该提案将通过研究艾滋病毒的潜在机制来扩展她目前由美国国立卫生研究院资助的研究目的 1A：确定是否具有克隆性不确定潜能造血 (CHIP) 突变在外周血细胞中更为普遍感染者与未感染对照；目标 1B：确定 CHIP 突变的存在是否相关根据 FDG- 评估，动脉炎症和造血系统代谢活动增加正电子断层扫描/计算机断层扫描；目标 2A：识别 PLWH 中与动脉相关的独特蛋白质组特征造血系统的炎症和代谢活动，目标 2B：表征造血系统的变化抗炎和脂质干预后改变的蛋白质和生物途径。这个提议将提供受试者访视、影像以及临床和实验室数据，以支持临床/ HIV相关CVD和HIV疾病发病机制（包括治愈）领域的转化研究。