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 徐博士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。 在过去的15年里，他一直在研究艾滋病毒背景下的心血管疾病(CVD)。最初的部分 她职业生涯的大部分时间是在扎克伯格旧金山综合医院(Zuckerberg San Francisco General)建立艾滋病心脏病诊所(ZSFG)， 2)开发基础设施以进行以患者为中心的心脏病学研究，包括开发 用于临床研究的血管实验室，3)进行评估艾滋病毒潜在机制的研究 感染和心血管疾病；4)；旨在降低艾滋病毒感染和心血管疾病风险的领先临床试验。这个 她的研究结果表明，1)艾滋病毒感染与心血管疾病独立相关，独立于 传统危险因素或抗逆转录病毒疗法和2)有效治疗艾滋病毒感染背景下的慢性炎症 这是简历风险增加的根本原因。最初的K24支持导致了学员数量的显著增加， 对徐博士的资助和出版物，以及新的研究方向，包括使用新的成像技术来评估 艾滋病毒疾病负担和确定治疗方法，以减少艾滋病毒相关炎症和心血管疾病风险。对于 K24更新期，她的职业目标是进行尖端的临床/翻译研究和指导 这将导致在治疗、识别和预防PLWH中的心血管疾病方面有所改进，并对其他 合并症和艾滋病毒的治疗。徐博士计划扩大她的研究范围，将体细胞突变的作用包括在内 在造血系统(称为不确定潜能的克隆性造血，芯片)和蛋白质组学中 与艾滋病毒相关的心血管疾病；2)继续在艾滋病毒感染领域指导初级调查人员， 炎症和心血管疾病，重点是过渡到完全独立；3)获得领导力培训，以建立 临床和转化性研究项目，可供学员使用，并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，该校为以下项目提供了出色的资源 临床/转化性研究、基础科学、成像、艾滋病毒和指导/领导力培训。她的K24 提案将通过研究艾滋病毒的潜在机制来扩展她目前由NIH资助的调查- 将接受治疗的HIV患者的动脉粥样硬化与以下特定目标相关联：目标1A：确定克隆性 不确定电位(CHIP)突变的造血功能在儿童的外周血细胞中更为常见 PLWH与未感染对照：目标1B：确定芯片突变的存在是否相关 随着动脉炎症和造血系统代谢活性的增加，FDG- PET/CT；目标2A：确定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，以及目标2B：表征 在抗炎和脂质干预后改变的蛋白质和生物途径。这项建议 将提供受试者访问、成像以及临床和实验室数据，以支持临床/ HIV相关心血管疾病和包括治疗在内的HIV疾病发病机制的翻译研究。