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
基本信息
- 批准号:10591934
- 负责人:
- 金额:$ 19.69万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AddressAffectAldosteroneAngiotensin IIAngiotensin ReceptorAngiotensin-Converting Enzyme InhibitorsAngiotensinogenAngiotensinsAttenuatedBiological MarkersCardiovascular DiseasesCharacteristicsCirculationClinicalClinical TrialsCrohn&aposs diseaseDataDevelopmentDiseaseDisease ProgressionDisease modelDrug ModulationEnzyme InhibitionEquilibriumFibrosisFunding MechanismsGoalsGranulomaGranulomatousGranulomatous diseaseHormonesHumanImmune responseIn VitroInflammationInflammatoryInterleukin-10Interstitial Lung DiseasesInvestigationKnowledgeLinkLungMacrophageMediatingMineralocorticoid ReceptorMissionModelingMolecularMolecular TargetMorphologyPathogenesisPathologicPathway interactionsPatientsPeptidyl-Dipeptidase APhagosomesPharmaceutical PreparationsPhenotypePilot ProjectsPlayPulmonary SarcoidosisReceptor ActivationRenin-Angiotensin-Aldosterone SystemResearchResearch DesignRoleSTAT3 geneSarcoidosisSignal PathwaySignal TransductionTherapeutic AgentsTimeTissuesUnited States National Institutes of Healthaspirateburden of illnessdisabilityeffective therapyexperiencehuman tissuein vitro Modelinhibitorinnovationinsightnew therapeutic targetnovelnovel markernovel therapeuticspotential biomarkerpredictive markerpredictive modelingprognosticationreceptorresponsetherapeutic targetvirtual
项目摘要
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
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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ELLIOTT D CROUSER其他文献
BLACK PATIENTS WITH AN ICD DIAGNOSIS OF SARCOIDOSIS HAVE LOWER PREVALENCE OF BIOPSY CONFIRMING SARCOIDOSIS COMPARED TO WHITE PATIENTS IN A SINGLE-CENTER RETROSPECTIVE COHORT
- DOI:
10.1016/j.chest.2024.06.2036 - 发表时间:
2024-10-01 - 期刊:
- 影响因子:
- 作者:
JASON KABIR;KALI MCKNIGHT;GENNARO DI TOSTO;MICHELLE SHARP;ELLIOTT D CROUSER;JOHN ODACKAL - 通讯作者:
JOHN ODACKAL
SARCOIDOSIS AND CVID: WHAT IS THE LINK?
- DOI:
10.1016/j.chest.2023.07.3601 - 发表时间:
2023-10-01 - 期刊:
- 影响因子:
- 作者:
SARAH M MACDOWELL;ARINDAM SINGHA;ELLIOTT D CROUSER - 通讯作者:
ELLIOTT D CROUSER
INCIDENCE OF POSTCHECKPOINT INHIBITOR SARCOIDOSIS: A SINGLE-CENTER OBSERVATIONAL STUDY
- DOI:
10.1016/j.chest.2022.08.2171 - 发表时间:
2022-10-01 - 期刊:
- 影响因子:
- 作者:
ROBERT EASTERLING;ARINDAM SINGHA;ELLIOTT D CROUSER;KEVIN HO - 通讯作者:
KEVIN HO
ELLIOTT D CROUSER的其他文献
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{{ truncateString('ELLIOTT D CROUSER', 18)}}的其他基金
Supplemental Citicoline Administration for Reduction of Lung Injury Efficacy Trial (SCARLET)
补充胞二磷胆碱减少肺损伤疗效试验(SCARLET)
- 批准号:
10657726 - 财政年份:2022
- 资助金额:
$ 19.69万 - 项目类别:
Supplemental Citicoline Administration for Reduction of Lung Injury Efficacy Trial (SCARLET)
补充胞二磷胆碱减少肺损伤疗效试验(SCARLET)
- 批准号:
10406027 - 财政年份:2022
- 资助金额:
$ 19.69万 - 项目类别:
Circulating Exosome microRNA as Markers of Severe Sarcoidosis Phenotypes
循环外泌体 microRNA 作为严重结节病表型的标志物
- 批准号:
9434044 - 财政年份:2017
- 资助金额:
$ 19.69万 - 项目类别:
Nicotine Treatment for Pulmonary Sarcoidosis: A Clinical Trial Pilot Study
尼古丁治疗肺结节病:临床试验试点研究
- 批准号:
8915741 - 财政年份:2014
- 资助金额:
$ 19.69万 - 项目类别:
Sarcoidosis Health Care Disparities and Clinical Research Challenges
结节病医疗保健差异和临床研究挑战
- 批准号:
8836634 - 财政年份:2014
- 资助金额:
$ 19.69万 - 项目类别:
Nicotine Treatment for Pulmonary Sarcoidosis: A Clinical Trial Pilot Study
尼古丁治疗肺结节病:临床试验试点研究
- 批准号:
8753389 - 财政年份:2014
- 资助金额:
$ 19.69万 - 项目类别:
Dendritic Cell Activation by Mitochondrial Transcription Factor A
线粒体转录因子 A 激活树突状细胞
- 批准号:
7707655 - 财政年份:2009
- 资助金额:
$ 19.69万 - 项目类别:
Dendritic Cell Activation by Mitochondrial Transcription Factor A
线粒体转录因子 A 激活树突状细胞
- 批准号:
7897735 - 财政年份:2009
- 资助金额:
$ 19.69万 - 项目类别:
Induction of Inflammation by Mitochondrial Proteins
线粒体蛋白诱导炎症
- 批准号:
7086145 - 财政年份:2005
- 资助金额:
$ 19.69万 - 项目类别:
Induction of Inflammation by Mitochondrial Proteins
线粒体蛋白诱导炎症
- 批准号:
6965294 - 财政年份:2005
- 资助金额:
$ 19.69万 - 项目类别:
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