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

• 批准号: 10578803
• 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
• 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/10578803
• 关键词: Anti-Inflammatory Agents; Atherosclerosis; Award; Basic Science; Biological; Blood Cells; Blood Vessels; Bone Marrow; Cardiology; Cardiovascular Diseases; Chronic; Clinic; Clinical; Clinical Data; Clinical Research; Clinical Trials; Coronary heart disease; Data; Development; Disease; Event; Extramedullary Hematopoiesis; 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; 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; improved; inflammatory marker; inhibitor; lymph nodes; mortality; multidisciplinary; novel; patient oriented; patient oriented research; prevent; progenitor; protein biomarkers; proteomic signature; stem cells; sudden cardiac death; translational research program; translational study

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.

项目摘要/摘要 Hsue博士是世界上为数不多的具有广泛研究和艾滋病毒临床专业知识的心脏病专家之一 在过去的15年中，研究心血管疾病（CVD）在HIV环境中。初始部分 她的职业生涯被花在了1）在扎克伯格旧金山将军（ZSFG）建立HIV心脏病学诊所， 2）开发基础设施以进行心脏病学以患者为导向的研究，包括开发 临床研究的血管实验室，3）进行评估HIV基础机制的研究 感染和CVD和4）；领先的临床试验旨在降低HIV中的炎症和CVD风险。这 她工作的发现表明1）艾滋病毒感染与CVD独立相关，独立于 传统的危险因素或艺术以及2）在有效治疗的艾滋病毒感染的情况下慢性炎症 这是CV风险增加的基础。最初的K24支持导致受训者的数量显着增加， 赠款和HSUE博士的出版物和新的研究指示，包括使用新成像来评估 HIV疾病负担和鉴定疗法，以减少与HIV相关的炎症和简历风险。为了 K24更新时期，她的职业目标是进行最前沿的临床/翻译研究和指导 这将导致改善PLWH之间的治疗，识别和预防CVD，并影响其他 合并症和艾滋病毒治愈方法。 Hsue博士计划1）扩大她的研究以包括躯体突变的作用 在造血系统（称为不确定潜力的克隆造血，芯片）和蛋白质组学中 与HIV相关的CVD； 2）继续花时间指导艾滋病毒感染领域的初级调查员， 炎症和CVD，重点是向全独立过渡； 3）获得领导培训以建立 可以由受训者使用的临床和转化研究计划，并将使她成为更好的导师。 Hsue博士的职业发展大多数将在UCSF发生，该发展为 临床/翻译研究，基础科学，成像，艾滋病毒和指导/领导力培训。她的K24 提案将通过研究HIV的潜在机制来扩展其目前的NIH资助调查 与治疗的HIV相关的动脉粥样硬化具有以下特定目的：AIM 1A：确定是否克隆 不确定电势（CHIP）突变的造血性突变在外周血细胞中更为普遍 PLWH与未感染的控件；目标1B：确定芯片突变的存在是否相关 随着造血系统的动脉炎症和代谢活性的增加，FDG- 宠物/CT; AIM 2A：确定与动脉相关的唯一蛋白质组学签名 造血系统的炎症和代谢活性，目标2B：以表征变化 抗炎和脂质干预后改变的蛋白质和生物途径。这个建议 将提供主题访问，成像以及临床和实验室数据，以支持临床/ HIV相关CVD和HIV疾病发病机理的转化研究，包括治疗。