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

项目总结/摘要 博士Hsue是世界上为数不多的心脏病专家之一，在艾滋病毒方面拥有广泛的研究和临床专业知识 在过去的15年里，他一直致力于研究艾滋病背景下的心血管疾病。原始组件 她的职业生涯花了1）在扎克伯格旧金山总医院（Zuckerberg San Francisco General）建立了一个艾滋病心脏病诊所， 2)发展基础设施，在心脏病学中进行以患者为导向的研究，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 感染和心血管疾病和4）;领先的临床试验，旨在减少炎症和心血管疾病的风险，在艾滋病毒。的 她的研究结果表明：1）HIV感染与CVD独立相关， 传统风险因素或ART和2）在有效治疗HIV感染的情况下的慢性炎症 这是CV风险增加的基础。最初的K24支持导致了学员人数的显著增加， 赠款，并为许博士和新的研究方向，包括使用新的成像评估出版物 HIV疾病负担和确定治疗方法，以减少HIV相关炎症和CV风险。为 K24续约期间，她的职业目标是进行尖端的临床/转化研究和指导 这将导致改善治疗，识别和预防艾滋病毒感染者的心血管疾病，并影响其他 合并症和艾滋病治愈。徐博士计划扩大她的研究范围，将体细胞突变的作用也包括在内 在造血系统（称为克隆造血的不确定潜力，CHIP）和蛋白质组学， 艾滋病毒相关的心血管疾病; 2）继续她在艾滋病毒感染领域指导初级研究人员的时间， 炎症和CVD，重点是过渡到完全独立; 3）获得领导力培训， 临床和转化研究项目，可以被学员使用，并将使她成为一个更好的导师。 许博士的大部分职业发展将发生在UCSF，它提供了优秀的资源， 临床/转化研究、基础科学、成像、艾滋病毒和指导/领导力培训。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NIH资助的研究， 以下是HIV治疗后相关动脉粥样硬化的具体目的：目的1A：确定是否存在克隆性 不确定潜能的造血（CHIP）突变在以下患者的外周血细胞中更普遍： PLWH vs.未感染对照;目的1B：确定CHIP突变的存在是否与PLWH的发生相关。 随着动脉炎症和造血系统代谢活性的增加， PET/CT;目的2A：确定PLWH中与动脉粥样硬化相关的独特蛋白质组特征 目的2B：表征造血系统的炎症和代谢活性的变化， 抗炎和脂质干预后改变的蛋白质和生物途径。这项建议 将提供受试者访视、成像以及临床和实验室数据，以支持新研究者进行临床/ 在HIV相关CVD和HIV疾病发病机制（包括治愈）领域的转化研究。

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.