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

基本信息

  • 批准号:
    9270934
  • 负责人:
  • 金额:
    $ 19.2万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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 这项建议将评估新的作用,肾素-血管紧张素-醛固酮系统(RAAS)激活的关键, HIV中炎症介导的心血管疾病(CVD)的驱动因素,代表了一个重要的 研究偏离了对RAAS调节钠的传统生理作用的理解 平衡和血量。与艾滋病无关的发病率和死亡率大幅上升, 在接受抗逆转录病毒疗法(ART)治疗的艾滋病毒患者中, 研究表明,与普通人群相比,HIV患者患CVD的风险增加了两倍。在 支持这一点的是,我们小组的心脏成像研究显示了关键证据,即HIV患者有一个 易损型冠状动脉斑块的患病率较高,更容易发炎和破裂。总的来说, ART和常规药物,如降脂和降糖药物的联合使用, 对降低HIV感染者的CVD风险完全有效。在这方面,目前没有FDA批准的策略, 可以显著降低HIV人群中CVD的风险。因此,艾滋病毒中的心血管疾病 公共卫生挑战,需要研究新的治疗靶点, 艾滋病毒相关机制。 在这方面,候选人的初步数据表明,艾滋病毒患者的醛固酮增加, 与非HIV个体相比, RAAS激活状态。此外,候选人已经表明,RAAS激活状态刺激亲- 艾滋病毒感染者的炎症环境。进行性炎症的一个重要后遗症是 动脉粥样硬化性疾病综上所述,这些新的数据表明,在HIV中存在一种独特的代谢表型, 与CVD的临床相关性,并为基于生理学的策略提供了强有力的理由, 通过盐皮质激素受体(MR)拮抗作用在HIV相关CVD中激活RAAS。在目标一,候选人 将使用复杂的算法对RAAS进行详细和受控的生理调查, 评估RAAS激活与RAAS抑制期间全身和血管炎症的差异 状态在目标II中,候选人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,首次评价 MR阻滞对HIV患者动脉炎症的影响本研究将使用心脏18F-FDG-PET/CT技术, 利用生物学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。两个目标将平行进行,但相互独立 这些探索将为评估RAAS生理学、炎症和CVD提供新的信息 在艾滋病人群中。 目前的K23提案是一个全面的五年培训计划,提供了一个出色的机制 获得职业发展指导奖候选人是一名训练有素的内分泌学家和教员 在马萨诸塞州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。候选人召集了一个 由医学博士Steven Grinspoon(马萨诸塞州总医院)和Gail Adler领导的强大指导团队 医学博士,博士(布里格姆妇女医院),在各自的艾滋病毒领域都得到国际认可 心血管疾病风险评估和盐皮质激素生理学和资金充足。此外,候选人将 在提供心血管成像领域复杂培训的多元化顾问团队的支持下, 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 代谢在马萨诸塞州总医院将提供全面的培训经验。的 候选人在其调查职业生涯的早期阶段表现出出色的生产力, 受益于先进的指导和指令,以解决这个赠款提案的新奇, 利用生理算法中的概念进行代谢表型分析,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风险的放射学方式 评估,免疫表型,和严格的数据处理纵向数据集。艾滋病毒是一种 获得性慢性炎症和心血管疾病,在这方面,这些研究和研究原则将作为 长期的高级临床和转化研究的范例,重点是激素 在艾滋病毒和其他高危人群中,包括肥胖症的进一步炎症过程中的贡献。与 最后,K23奖的资助将使候选人继续沿着有希望的轨道前进 作为一名临床科学家,在以病人为导向的研究中走向独立。

项目成果

期刊论文数量(0)
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Suman Srinivasa其他文献

Suman Srinivasa的其他文献

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{{ truncateString('Suman Srinivasa', 18)}}的其他基金

Avoiding (Heart) Failure: Physiologic-Based Targeting of the RAAS to Treat Subclinical HFpEF among PWH
避免(心)力衰竭:基于生理学的 RAAS 靶向治疗感染者中的亚临床 HFpEF
  • 批准号:
    9927067
  • 财政年份:
    2020
  • 资助金额:
    $ 19.2万
  • 项目类别:
Avoiding (Heart) Failure: Physiologic-Based Targeting of the RAAS to Treat Subclinical HFpEF among PWH
避免(心)力衰竭:基于生理学的 RAAS 靶向治疗感染者中的亚临床 HFpEF
  • 批准号:
    10084314
  • 财政年份:
    2020
  • 资助金额:
    $ 19.2万
  • 项目类别:
Avoiding (Heart) Failure: Physiologic-Based Targeting of the RAAS to Treat Subclinical HFpEF among PWH
避免(心)力衰竭:基于生理学的 RAAS 靶向治疗感染者中的亚临床 HFpEF
  • 批准号:
    10533826
  • 财政年份:
    2020
  • 资助金额:
    $ 19.2万
  • 项目类别:
Avoiding (Heart) Failure: Physiologic-Based Targeting of the RAAS to Treat Subclinical HFpEF among PWH
避免(心)力衰竭:基于生理学的 RAAS 靶向治疗感染者中的亚临床 HFpEF
  • 批准号:
    10323258
  • 财政年份:
    2020
  • 资助金额:
    $ 19.2万
  • 项目类别:
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:
    10079022
  • 财政年份:
    2017
  • 资助金额:
    $ 19.2万
  • 项目类别:
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
  • 财政年份:
    2017
  • 资助金额:
    $ 19.2万
  • 项目类别:

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制定针对醛固酮和 AGEs-RAGE 轴的治疗策略,以阻止肾脏疾病的进展
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  • 批准号:
    10600520
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    2023
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醛固酮/盐皮质激素受体对生物性别和盐摄入量的反应:赖氨酸特异性脱甲基酶 1 (LSD1) 的作用
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开发用于高灵敏度对产生醛固酮的腺瘤进行成像的 CYP11B2 探针。
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醛固酮阻断用于终末期肾病健康改善评估:延伸
  • 批准号:
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利钠肽-肾素-血管紧张素-醛固酮系统节律轴与夜间血压
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    10545747
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    2022
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    $ 19.2万
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Natriuretic Peptide-Renin-Angiotensin-Aldosterone System Rhythm Axis and Nocturnal Blood Pressure
利钠肽-肾素-血管紧张素-醛固酮系统节律轴与夜间血压
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    10342142
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