Role of Renin-Angiotensin-Aldosterone System during sarcoidosis granuloma formation

肾素-血管紧张素-醛固酮系统在结节病肉芽肿形成过程中的作用

• 批准号: 10591934
• 负责人: ELLIOTT D CROUSER
• 金额: $ 19.69万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-11-18 至 2024-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10591934
• 关键词: Address; Affect; Aldosterone; Angiotensin II; Angiotensin Receptor; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Angiotensins; Attenuated; Biological Markers; Cardiovascular Diseases; Characteristics; Circulation; Clinical; Clinical Trials; Crohn' s disease; Data; Development; Disease; Disease Progression; Disease model; Drug Modulation; Enzyme Inhibition; Equilibrium; Fibrosis; Funding Mechanisms; Goals; Granuloma; Granulomatous; Granulomatous disease; Hormones; Human; Immune response; In Vitro; Inflammation; Inflammatory; Interleukin-10; Interstitial Lung Diseases; Investigation; Knowledge; Link; Lung; Macrophage; Mediating; Mineralocorticoid Receptor; Mission; Modeling; Molecular; Molecular Target; Morphology; Pathogenesis; Pathologic; Pathway interactions; Patients; Peptidyl-Dipeptidase A; Phagosomes; Pharmaceutical Preparations; Phenotype; Pilot Projects; Play; Pulmonary Sarcoidosis; Receptor Activation; Renin-Angiotensin-Aldosterone System; Research; Research Design; Role; STAT3 gene; Sarcoidosis; Signal Pathway; Signal Transduction; Therapeutic Agents; Time; Tissues; United States National Institutes of Health; aspirate; burden of illness; disability; effective therapy; experience; human tissue; in vitro Model; inhibitor; innovation; insight; new therapeutic target; novel; novel marker; novel therapeutics; potential biomarker; predictive marker; predictive modeling; prognostication; receptor; response; therapeutic target; virtual

Sarcoidosis is a pulmonary and systemic granulomatous disease of unknown cause. To better understand disease mechanisms, we have recently established a novel in vitro human granuloma model that shares many structural and molecular features of the disease in human tissues, yielding novel insights into mechanisms regulating early granuloma formation. In keeping with prior investigations and clinical experience linking sarcoidosis to elevated leves of angiotensin converting enzyme (ACE) in sarcoidosis tissues, molecular characterization of the sarcoidosis granuloma model indicates that macrophages participating in sarcoidosis granuloma formation are regulated by the renin-angiotensin-aldosterone system (RAAS). Our strong preliminary data shows that sarcoidosis macrophages produce aldosterone, a hormone that promotes inflammation through the activation of mineralocorticoid receptors (MRs); and we further show that suppression of the RAAS pathway (e.g., ACE inhibition) or inhibition of MRs attenuates granuloma formation. We hypothesize that RAAS promotes pathological granuloma formation in patients with sarcoidosis through activation of MRs. In the spirit of the R21 funding mechanisms, this project is highly innovative and has important beneficial implications for advancing our understanding of sarcoidosis disease mechanisms and for providing novel therapeutic targets and disease biomarkers. Aim 1 will determine if the balance between ACE1 and ACE2 (a suppressor of ACE1-mediated inflammation) regulates sarcoidosis granuloma formation by controlling angiotensin II levels and related angiotensin 1 receptor (ATR1) activation. We posit that the balance between ACE and ACE2 influences the formation of granulomas in sarcoidosis patients. Aim 2 will determine if aldosterone induced MR activation promotes NRF2/HO-1/STAT3 signaling to promote sarcoidosis granuloma formation, featuring polarization towards CD163 macrophages. These studies will determine if aldosterone promotes macrophage phagosome-activated signaling pathway NRF2/HO-1/STAT3 to polarize macrophages towards a CD163 expressing phenotype that is predisposed to aggregate and form granulomas. Aim 3 will be a pilot study designed to determine if aldosterone levels achieved in the in vitro granuloma model are predictive of pulmonary sarcoidosis disease progression. Currently, there are no reliable biomarkers predictive of sarcoidosis disease progression for prognostication and to guide therapy, and aldosterone is a viable candidate. The short-term goals of this are to advancing basic understanding of sarcoidosis disease mechanisms and to consider related therapeutic targets. Long-term aspirations of this project are to address current deficiencies in the field of sarcoidosis as relates to identifying novel disease-specific therapies (targeting granuloma formation), identifying novel biomarkers predictive of disease progression, and to ultimately determine if it is feasible to repurpose widely available RAAS modulating drugs (e.g., ACE, ATR1 and MR inhibitors) for the treatment of sarcoidosis.

结节病是一种病因不明的肺部和全身肉芽肿性疾病。为了更好地理解