Physiologic Investigation of the Renin-Angiotensin-Aldosterone System to Understand Arterial Inflammation in HIV

通过肾素-血管紧张素-醛固酮系统的生理学研究来了解 HIV 患者的动脉炎症

• 批准号: 9270934
• 负责人: Suman Srinivasa
• 金额: $ 19.2万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-25 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9270934
• 关键词: Address; Aldosterone; Algorithms; Anti-Inflammatory Agents; Anti-Retroviral Agents; Applications Grants; Area; Arterial Fatty Streak; Atherosclerosis; Award; Blood Volume; CCL2 gene; Cardiac; Cardiology; Cardiovascular Diseases; Cardiovascular system; Cells; Chronic; Clinical; Coronary; Data; Development; Diagnostic radiologic examination; Diet; Dietary Sodium; Disease; Doctor of Philosophy; Endocrine system; Endocrinologist; Endocrinology; Equilibrium; FDA approved; Faculty; Fatty acid glycerol esters; Fibrosis; Funding; General Hospitals; General Population; Glucose; HIV; HIV Infections; HIV Receptors; Heart; Heart Diseases; High Prevalence; Hormonal; Hormones; Hospitals; IL6 gene; Imaging Techniques; Immunologic Markers; Immunologics; Immunology; Immunophenotyping; In Situ; Individual; Inflammation; Inflammatory; Instruction; Insulin Resistance; International; Investigation; K-Series Research Career Programs; Knowledge; Link; Lipids; Macrophage Activation; Massachusetts; Measures; Mediating; Mediator of activation protein; Mentored Patient-Oriented Research Career Development Award; Mentors; Mentorship; Metabolic; Metabolism; Mineralocorticoid Receptor; Mineralocorticoids; Modality; Modeling; Morbidity - disease rate; Morphology; Myocardial; Myocarditis; Nutritional; Obesity; PET/CT scan; Pathologic; Pathology; Patients; Pharmaceutical Preparations; Phenotype; Physiological; Physiology; Placebos; Population; Populations at Risk; Process; Productivity; Public Health; Randomized; Randomized Controlled Trials; Receptor Activation; Regulation; Renin-Angiotensin-Aldosterone System; Research; Research Infrastructure; Resources; Risk; Risk Assessment; Risk Factors; Risk Reduction; Role; Rupture; Safety; Science; Scientist; Secondary to; Serum; Sodium; Sum; Surface; System; Technology; Time; Tissues; Training; Training Programs; United States National Institutes of Health; Vascular Diseases; Visceral; Woman; abdominal fat; antiretroviral therapy; base; cardiovascular disorder risk; cardiovascular health; cardiovascular imaging; cardiovascular visualization; career; catalyst; circulating biomarkers; clinically relevant; design; dietary control; disorder risk; double-blind placebo controlled trial; eplerenone; experience; fluorodeoxyglucose positron emission tomography; glucose uptake; high risk; imaging biomarker; imaging study; immune activation; improved; indexing; inflammatory milieu; lipoprotein-associated phospholipase A(2); longitudinal dataset; macrophage; medical schools; member; metabolic phenotype; mortality; new therapeutic target; novel; nutrition; patient oriented research; programs; randomized placebo controlled trial; statistics; targeted treatment; tool; treatment strategy; vascular inflammation; waist circumference

Project Summary This proposal will evaluate the novel role of renin-angiotensin-aldosterone system (RAAS) activation as a key driver of inflammatory mediated cardiovascular disease (CVD) in HIV and represents a substantial investigative departure from understanding the traditional physiologic role of the RAAS in regulating sodium balance and blood volume. There is a considerable rise in non-AIDS related morbidity and mortality secondary to cardiovascular complications among those HIV patients well treated on antiretroviral therapy (ART), and studies show that HIV patients are at a two-fold increased risk for CVD compared to the general population. In support of this, cardiac imaging studies from our group demonstrate critical evidence that HIV patients have a higher prevalence of a vulnerable type of coronary plaque, more inflamed and prone to rupture. Overall, combined use of ART and conventional agents, such lipid and glucose lowering medications, are not completely effective for CVD risk reduction in HIV. In this regard, no current FDA approved strategies are available to significantly lower the risk of CVD in the HIV population. Therefore, CVD in HIV presents an unmet public health challenge that demands investigation of a novel therapeutic target, which importantly leverages an HIV-related mechanism. In this regard, preliminary data from the Candidate demonstrate that HIV patients have increased aldosterone in association with excess visceral adiposity and insulin resistance compared to non-HIV individuals during a RAAS activated state. Moreover, the Candidate has shown that the RAAS activated state stimulates a pro- inflammatory milieu among the HIV population. An important sequela of progressive inflammation is atherosclerotic disease. Taken together, these novel data suggest a unique metabolic phenotype in HIV with clinical relevance to CVD and provides the strong rationale for a physiologically based strategy to reduce RAAS activation in HIV-related CVD via mineralocorticoid receptor (MR) antagonism. In Aim I, the Candidate will perform a detailed and controlled physiologic investigation of the RAAS using sophisticated algorithms to assess differences in generalized and vascular inflammation during a RAAS activated vs. RAAS suppressed state. In Aim II, the Candidate will evaluate the clinical benefit of manipulating this hormonal system through implementation of a randomized, double-blinded placebo controlled trial evaluating first in the field effects of MR blockade on arterial inflammation in HIV. This study will use cardiac 18F-FDG-PET/CT technology, which takes advantage of a biologic approach to identify macrophage-rich vulnerable plaque through active tissue metabolism, to characterize arterial inflammation. Both Aims will be conducted in parallel, but are independent explorations that will provide new information to the field assessing RAAS physiology, inflammation, and CVD in the HIV population. The current K23 proposal is a comprehensive five year training plan that presents an outstanding mechanism for a mentored career development award. The Candidate is a trained Endocrinologist and faculty member within the Division of Endocrinology at the Massachusetts General Hospital and Harvard Medical School with an investigative focus on mechanisms for cardiometabolic disease in HIV. The Candidate has assembled a robust mentoring team headed by Steven Grinspoon, MD (Massachusetts General Hospital) and Gail Adler MD, PhD (Brigham and Women's Hospital), both internationally recognized in their respective fields of HIV CVD risk assessment and mineralocorticoid physiology and well-funded. In addition, the Candidate will be supported by a diverse team of advisors providing sophisticated training in areas of cardiovascular imaging, biomarker science, nutrition and metabolism, HIV immunology and statistics. Moreover, the research infrastructure and educational tools available through the Harvard Catalyst and the Program in Nutritional Metabolism at Massachusetts General Hospital will provide a comprehensive training experience. The Candidate has demonstrated outstanding productivity in the early stages of her investigative career and would benefit from advanced mentorship and instruction to address the novelty of this grant proposal, which leverages concepts in physiologic algorithms for metabolic phenotyping, regulation and safety of a randomized controlled trial, mineralocorticoid systems physiology, radiographic modalities for non-invasive CVD risk assessment, immunophenotyping, and rigorous data handling for longitudinal data sets. HIV is a model of acquired chronic inflammation and CVD, and in this regard, these studies and research principles will serve as a paradigm in the long-term for advanced clinical and translational investigations focused on hormonal contributions to further inflammatory processes in HIV and other at risk populations, including obesity. To that end, funding from the K23 award will critically allow the Candidate to continue on a promising trajectory towards independence as a clinician scientist in patient-oriented research.

项目概要 该提案将评估肾素-血管紧张素-醛固酮系统（RAAS）激活作为关键的新作用 HIV 中炎症介导的心血管疾病 (CVD) 的驱动因素，代表了重要的 研究偏离了 RAAS 在调节钠方面的传统生理作用 平衡和血容量。非艾滋病相关的发病率和死亡率显着上升 接受抗逆转录病毒治疗（ART）良好的艾滋病毒患者的心血管并发症，以及 研究表明，与普通人群相比，艾滋病毒患者患心血管疾病的风险增加两倍。在 为了支持这一点，我们小组的心脏成像研究证明了艾滋病毒患者有一个重要的证据 易损型冠状动脉斑块的患病率更高，更容易发炎且更容易破裂。全面的， 联合使用 ART 和常规药物（例如降脂和降糖药物）并不 对于降低 HIV 的 CVD 风险完全有效。在这方面，目前 FDA 还没有批准的策略 可显着降低艾滋病毒人群患心血管疾病的风险。因此，HIV 中的 CVD 是一个未得到满足的问题 公共卫生挑战需要研究新的治疗靶点，这重要的是利用 HIV相关机制。 在这方面，候选者的初步数据表明，HIV患者的醛固酮水平有所升高 与非艾滋病毒个体相比，与过度内脏肥胖和胰岛素抵抗相关 RAAS 激活状态。此外，候选人已表明 RAAS 激活状态会刺激亲 HIV 人群中的炎症环境。进行性炎症的一个重要后遗症是 动脉粥样硬化疾病。总而言之，这些新数据表明 HIV 具有独特的代谢表型 与 CVD 的临床相关性，并为基于生理的策略减少 通过盐皮质激素受体 (MR) 拮抗作用激活 HIV 相关 CVD 中的 RAAS。在“目标一”中，候选人 将使用复杂的算法对 RAAS 进行详细且受控的生理研究 评估 RAAS 激活与 RAAS 抑制期间全身炎症和血管炎症的差异 状态。在目标 II 中，考生将通过以下方式评估操纵该激素系统的临床益处： 实施一项随机、双盲安慰剂对照试验，首先评估现场效果 MR 阻断 HIV 动脉炎症。本研究将使用心脏 18F-FDG-PET/CT 技术，该技术 利用生物方法通过活性组织识别富含巨噬细胞的易损斑块 代谢，以表征动脉炎症。两个目标将同时进行，但相互独立 将为评估 RAAS 生理学、炎症和 CVD 领域提供新信息的探索 在艾滋病毒人群中。 目前的K23提案是一个全面的五年培训计划，提出了一个出色的机制 获得指导职业发展奖。候选人是一位训练有素的内分泌学家和教职人员 麻省总医院和哈佛医学院内分泌科 研究重点是艾滋病毒心脏代谢疾病的机制。候选人已经组建了一个 由 Steven Grinspoon 医学博士（马萨诸塞州总医院）和 Gail Adler 领导的强大指导团队 MD、PhD（布莱根妇女医院），均在各自的艾滋病毒领域获得国际认可 CVD风险评估和盐皮质激素生理学研究资金充足。此外，候选人将 由多元化的顾问团队提供支持，提供心血管成像领域的复杂培训， 生物标志物科学、营养和代谢、艾滋病毒免疫学和统计学。此外，研究 通过哈佛催化剂和营养计划提供的基础设施和教育工具 马萨诸塞州综合医院的新陈代谢将提供全面的培训体验。这 候选人在其调查生涯的早期阶段就表现出了出色的生产力，并将 受益于先进的指导和指导来解决这项拨款提案的新颖性， 利用生理算法中的概念进行随机代谢表型、调节和安全性 对照试验、盐皮质激素系统生理学、非侵入性 CVD 风险的放射照相方式 纵向数据集的评估、免疫表型分析和严格的数据处理。艾滋病毒是一个模型 获得性慢性炎症和CVD，在这方面，这些研究和研究原则将作为 专注于激素的高级临床和转化研究的长期范例 促进艾滋病毒和其他高危人群（包括肥胖）的进一步炎症过程。对此 最后，K23 奖项的资助将至关重要地让候选人继续走上有希望的轨道 作为临床科学家在以患者为导向的研究中走向独立。