Strategies for Angiotensin Receptor Blocker Mediated Tissue Repair

血管紧张素受体阻滞剂介导的组织修复策略

• 批准号: 10469311
• 负责人: Enid R Neptune
• 金额: $ 69.38万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-06 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10469311
• 关键词: Adult; Agonist; Alleles; Alveolar; Alveolar Cell; Angiotensin Receptor; Angiotensins; Animal Model; Anti-Inflammatory Agents; Apoptosis; Architecture; Attenuated; Biological Markers; Biological Models; Blood; Blood specimen; CYP2C9 gene; CYP3A4 gene; Cause of Death; Cell Survival; Cell model; Cells; Chronic; Chronic Obstructive Pulmonary Disease; Cigarette smoke-induced emphysema; Clinical; Cohort Studies; Data; Disease; Disease Progression; Enzymes; Epithelial Cells; Fibroblasts; Genetic; Genetic Determinism; Genotype; Goals; Human; Inflammation; Inflammatory; Injury; Intervention; Ligands; Losartan; Lung; Lung diseases; Mediating; Modeling; Morphology; Multicenter Studies; Mus; Natural regeneration; Observational Study; Outcome; Oxidative Stress; PPAR gamma; Participant; Pathway interactions; Patients; Persons; Production; Publishing; Pulmonary Emphysema; Pulmonary Inflammation; Randomized; Reporter; Role; Sampling; Signal Transduction; Smoke; Therapeutic; Time; Transforming Growth Factor beta; United States; United States National Institutes of Health; Variant; alveolar epithelium; antagonist; base; beta-arrestin; candidate marker; cell injury; cigarette smoke; cigarette smoke-induced; cigarette smoke-induced lung injury; cohort; double-blind placebo controlled trial; drug efficacy; exposure to cigarette smoke; improved; indexing; inhibitor; knock-down; lung injury; mouse model; mutant; overexpression; receptor; reduce symptoms; regenerative; repair strategy; repaired; reverse genetics; synergism; tissue repair; transcriptome sequencing; tsk mouse

Project Summary COPD/emphysema, the fourth leading cause of death in the US, is a chronic inflammatory lung disorder usually triggered by long-term cigarette smoke exposure. Although many therapies reduce the symptoms of COPD, no interventions exist which arrest or reverse the extensive architectural and functional damage that punctuate the disorder. Thus, therapies which not only reduce inflammation but also promote alveolar repair (resident cell survival, regenerative matrix production) are ideally suited for COPD efficacy. Angiotensin receptor blockers fulfill this dual role. The scientific premise is anchored on findings that: 1) angiotensin receptor blockade reverses genetic emphysema and protects against cigarette smoke induced emphysema in animal models manifest in reduced inflammation, reduced alveolar cell apoptosis and improved matrix morphology and 2) supportive observational studies and a randomized double-blinded placebo controlled trial of the angiotensin receptor blocker (ARB) Losartan (LOS) conducted under an NIH SCCOR mechanism that showed reversal or stabilization of emphysema in a subset of treated patients with established disease over a one year time frame. Such findings have led to an NIH-sponsored multicenter study of LOS in a cohort of patients with established emphysema (LEEP Trial). These data importantly suggest an unanticipated alveolar protective and reparative mechanism attached to angiotensin receptor blockade. Studies show that the antagonism of TGFβ signaling induced by cigarette smoke (CS) or genetic perturbation is a direct ARB- mediated protective mechanism in experimental emphysema. New preliminary data presented in current proposal implicate enhanced PPARγ signaling by ARBs as a parallel and potentially reinforcing mechanism (to TGFβ antagonism) for protection against CS-induced lung injury. LOS metabolites EXP3174 (3174) and EXP3179 (3179) selectively activate AT1R-dependent and AT1R-independent cascades, respectively, in both cell and animal model systems. Whereas AT1R-dependent repair engages selective antagonism of TGFβ signaling, AT1R-independent repair promotes PPARγ agonism and antiinflammatory signaling. Aim 1 studies delineate how LOS as a prototypical ARB attenuates CS-induced lung inflammation and injury and promotes alveolar repair via coordinated activation of PPARγ plus inhibition of TGFβ. Aim 2 studies establish how ARBs, via AT1R-dependent and -independent mechanisms, inhibit TGFβ cascades to modulate alveolar resident cell survival and airspace repair in setting of CS-induced lung injury. Aim 3 studies utilize blood samples from LEEP trial enrollees treated with LOS to 1) establish whether blood LOS and metabolite levels associate with TGFβ and PPARγ pathway biomarkers and 2) identify CYP variants that associate with metabolite levels. The proposed aims use primary cell models, experimental murine models and clinical samples from patients with emphysema treated with LOS to clarify the strategy by which ARBs promote airspace regeneration and also identify mechanisms for LOS metabolite production and their utility as precision biomarkers.

项目摘要 COPD/Emphysema是美国第四大死亡原因，是一种慢性炎性肺疾病 通常是由长期的香烟烟雾曝光引发的。尽管许多疗法减少了 COPD，不存在任何干预措施，可以阻止或扭转广泛的建筑和功能损害 打断疾病。那不仅减少炎症，还可以促进肺泡修复 （驻留细胞存活，再生基质产生）非常适合COPD效率。血管紧张素 接收器阻滞剂履行了这一双重角色。科学前提是基于：1）血管紧张素的发现 受体阻滞逆转遗传性肺气肿，并防止香烟烟雾诱发肺气肿 动物模型表现出减少的炎症，减少肺泡细胞凋亡和改善的基质 形态和2）支持观察性研究和随机双盲安慰剂对照试验 血管紧张素接收器阻滞剂（ARB）Losartan（LOS）（LOS）在NIH SCCOR机制下进行 显示了在A的一部分患者的一部分中，表现出肺气肿的逆转或稳定 一年的时间范围。这样的发现导致了NIH赞助的多中心研究，对 肺气肿的患者（LEEP试验）。这些数据重要地表明意外的肺泡 附着在血管紧张素受体阻断上的保护性和修复机制。研究表明 香烟烟雾（CS）或遗传扰动引起的TGFβ信号传导的拮抗作用是直接的ARB- 实验性肺气肿中介导的保护机制。当前显示的新初步数据 提案暗示ARB的PPARγ信号增强是一种平行且潜在的增强机制（TO TO TGFβ拮抗作用）可防止CS诱导的肺损伤。 LOS代谢物EXP3174（3174）和 EXP3179（3179）分别选择性激活AT1R依赖性和AT1R独立的级联反应 细胞和动物模型系统。而AT1R依赖性修复与TGFβ的选择性拮抗作用 信号传导，非AT1R独立修复会促进PPARγ激动剂和抗炎信号传导。 AIM 1研究 描述LOS作为原型ARB如何减弱CS诱导的肺部感染和损伤并促进 通过PPARγ的协调激活以及TGFβ的抑制作用，肺泡修复。 AIM 2研究确定了ARB的方式， 通过AT1R依赖性和非依赖性机制，抑制TGFβ级联反应调节肺泡居民细胞 在CS诱导的肺损伤的情况下，生存和空域修复。 AIM 3研究利用了血液样本 LOEP试验注册了LOS处理的1）确定血液LOS和代谢物水平是否与 TGFβ和PPARγ途径生物标志物以及2）识别与代谢物水平相关的CYP变体。 拟议的目的是使用患者的主要细胞模型，实验性鼠模型和临床样本 用LOS处理肺气肿，以阐明ARB促进空域再生的策略和 还要确定LOS代谢产物生产的机制及其作为精确生物标志物的实用性。