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: 9417077
• 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/9417077
• 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; 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; cardiometabolism; cardiovascular disorder risk; cardiovascular health; cardiovascular imaging; career; catalyst; circulating biomarkers; clinically relevant; coronary plaque; design; double-blind placebo controlled trial; eplerenone; experience; fluorodeoxyglucose; fluorodeoxyglucose positron emission tomography; glucose uptake; heart imaging; 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.

项目摘要 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 艾滋病毒中炎症性介导的心血管疾病（CVD）的驱动因素，代表了实质性的 调查性偏离理解RAA在调节钠中的传统生理作用 平衡和血液量。非AID相关的发病率和死亡率下降大幅上升 在接受抗逆转录病毒疗法（ART）治疗良好治疗的HIV患者中的心血管并发症和 研究表明，与普通人群相比，HIV患者的CVD风险增加了两倍。在 对此的支持，我们小组的心脏成像研究表明，艾滋病毒患者患有艾滋病毒患者的关键证据 易受伤害的冠状动脉斑块的患病率更高，更具发炎和容易破裂。全面的， 艺术和常规剂的联合使用，例如脂质和葡萄糖降低药物，不是 对于CVD降低艾滋病毒的风险完全有效。在这方面，当前没有FDA批准的策略是 可显着降低HIV人群中CVD的风险。因此，艾滋病毒中的CVD呈现未满足的 需要调查新型治疗靶标的公共卫生挑战，重要的是 与HIV相关的机制。 在这方面，候选人的初步数据表明艾滋病毒患者增加了醛固酮 与非HIV个体相比 RAAS激活状态。此外，候选人表明，RAA激活的状态刺激了促进状态 艾滋病毒人群中的炎症环境。进行性炎症的重要续集是 动脉粥样硬化疾病。综上所述，这些新颖的数据表明艾滋病毒中独特的代谢表型 与CVD的临床相关性，并为基于生理的策略提供了强有力的理由 通过盐皮质激素受体（MR）拮抗作用，与HIV相关的CVD中的RAAS激活。在目标一世中，候选人 将使用复杂的算法对RAA进行详细和控制的生理研究 评估RAAS激活与RAAS抑制过程中广义和血管炎症的差异 状态。在AIM II中，候选人将评估通过 在现场效果中首先评估的随机，双盲安慰剂对照试验的实施 艾滋病毒中动脉炎症的MR封锁。这项研究将使用心脏18F-FDG-PET/CT技术， 利用生物学方法来鉴定通过活性组织识别巨大的易受攻击的斑块 代谢，以动脉炎症为特征。这两个目标都将并行进行，但是独立的 探索将为评估RAAS生理，炎症和CVD的现场提供新信息的探索 在艾滋病毒人群中。 当前的K23提案是一项全面的五年培训计划，呈现出杰出的机制 获得指导的职业发展奖。候选人是训练有素的内分泌学家和教职员工 在马萨诸塞州综合医院和哈佛医学院的内分泌学划分中 调查性重点是HIV中心脏代谢疾病的机制。候选人组装了 强大的指导团队由马里兰州史蒂文·格林斯彭（MASCACHUSETTS综合医院）和盖尔·阿德勒（Gail Adler）领导 医学博士，博士学位（杨百翰和妇女医院），两者在各自的艾滋病毒领域都在国际上认可 CVD风险评估和矿物皮质生理学和资金充足。此外，候选人将是 在一个多元化的顾问团队的支持下，在心血管成像领域提供复杂的培训， 生物标志物科学，营养和代谢，HIV免疫学和统计。而且，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代谢将提供全面的培训经验。这 候选人在调查生涯的早期阶段表现出出色的生产力，并将 从高级指导和指导中受益，以解决该赠款提案的新颖性，该提案的新颖性 在生理算法中利用概念，用于代谢表型，调节和安全性 对照试验，矿物皮质系统生理学，非侵入性CVD风险的放射学方式 评估，免疫表型和纵向数据集的严格数据处理。艾滋病毒是 获得了慢性炎症和CVD，在这方面，这些研究和研究原则将作为 长期用于荷尔蒙的高级临床和翻译研究的范式 包括肥胖症在内的艾滋病毒和其他处于风险种群中的进一步炎症过程的贡献。为此 结束时，K23奖的资金将批判性地允许候选人继续进行有前途的轨迹 作为以患者为导向的研究的临床科学家的独立性。