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.

项目概要 慢性阻塞性肺病/肺气肿是一种慢性炎症性肺部疾病，是美国第四大死因 通常是由长期接触香烟烟雾引发的。尽管许多疗法可以减轻症状 慢性阻塞性肺病，不存在任何干预措施可以阻止或逆转广泛的建筑和功能损伤 标点障碍。因此，治疗不仅可以减少炎症，还可以促进肺泡修复 （常驻细胞存活、再生基质产生）非常适合慢性阻塞性肺病（COPD）疗效。血管紧张素 受体阻滞剂发挥这种双重作用。科学前提基于以下发现：1) 血管紧张素 受体阻断可逆转遗传性肺气肿并预防吸烟引起的肺气肿 动物模型表现为炎症减轻、肺泡细胞凋亡减少和基质改善 形态学和 2) 支持性观察研究和随机双盲安慰剂对照试验 在 NIH SCCOR 机制下进行的血管紧张素受体阻滞剂 (ARB) 洛沙坦 (LOS) 的研究 结果表明，在一段时间内患有既定疾病的接受治疗的患者中，肺气肿得到逆转或稳定。 一年的时间范围。这些发现导致了 NIH 资助的一项针对 LOS 的多中心研究。 患有肺气肿的患者（LEEP 试验）。这些数据重要地表明了意想不到的肺泡 与血管紧张素受体阻断相关的保护和修复机制。研究表明， 由香烟烟雾 (CS) 或遗传扰动诱导的 TGFβ 信号传导的拮抗作用是直接的 ARB- 实验性肺气肿介导的保护机制。当前提供的新初步数据 提案暗示 ARB 增强的 PPARγ 信号传导是一种平行且潜在的增强机制（以 TGFβ 拮抗作用）可预防 CS 引起的肺损伤。 LOS 代谢物 EXP3174 (3174) 和 EXP3179 (3179) 分别选择性激活 AT1R 依赖性和 AT1R 独立级联， 细胞和动物模型系统。而 AT1R 依赖性修复会选择性拮抗 TGFβ AT1R 独立修复可促进 PPARγ 激动和抗炎信号传导。目标 1 研究 描述 LOS 作为一种典型的 ARB 如何减轻 CS 引起的肺部炎症和损伤并促进 通过协调激活 PPARγ 和抑制 TGFβ 来修复肺泡。目标 2 研究确定了 ARB 如何 通过 AT1R 依赖和独立机制，抑制 TGFβ 级联反应来调节肺泡驻留细胞 CS 引起的肺损伤中的生存和空腔修复。目标 3 研究利用来自 接受 LOS 治疗的 LEEP 试验参与者 1) 确定血液 LOS 和代谢水平是否与 TGFβ 和 PPARγ 通路生物标志物以及 2) 识别与代谢水平相关的 CYP 变异。 拟议的目标使用原代细胞模型、实验鼠模型和来自患者的临床样本 用 LOS 治疗肺气肿，以阐明 ARB 促进空域再生的策略和 还确定了 LOS 代谢物产生的机制及其作为精确生物标志物的用途。