PPAR gamma as a therapeutic target in COPD

PPAR γ 作为 COPD 的治疗靶点

• 批准号: 8451900
• 负责人: THOMAS J MARIANI
• 金额: $ 37.01万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-05 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8451900
• 关键词: Address; Affect; Animal Disease Models; Animal Model; Asthma; Biological Availability; Boston; Cause of Death; Cells; Chemicals; Chronic; Chronic Obstructive Airway Disease; Cigarette smoke-induced emphysema; Cohort Studies; Data; Defect; Development; Disease; Disease susceptibility; Drug Targeting; Drug usage; Effector Cell; Epithelial; Epithelial Cells; Epithelium; Exposure to; FDA approved; Family; Gene Expression; Gene Targeting; Genes; Genetic Variation; Human; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Injury; Ligands; Lung; Lung Inflammation; Lung diseases; Macrophage Activation; Mediating; Metalloproteases; Molecular; Morbidity - disease rate; Mus; Organ; PPAR gamma; Pathogenesis; Pathology; Pathway interactions; Patients; Peroxisome Proliferator-Activated Receptors; Pharmacologic Substance; Phase II Clinical Trials; Phenotype; Physiological; Pre-Clinical Model; Predisposition; Pulmonary Emphysema; Pulmonary Fibrosis; Regulation; Reporting; Role; Smoke; Smoker; Structure; Structure of parenchyma of lung; Testing; Therapeutic; Therapeutic Effect; Therapeutic Intervention; Tissues; United States; Variant; Wild Type Mouse; base; cell type; chemokine; cigarette smoke-induced; cigarette smoking; disease phenotype; disorder control; early onset; human subject; human tissue; improved; in vivo; interest; loss of function; lung injury; lung maturation; macrophage; morphometry; mouse model; new therapeutic target; novel; pre-clinical; research study; response; response to injury; therapeutic target

DESCRIPTION (provided by applicant): An improved understanding of the mechanisms leading to COPD pathogenesis, as well as novel targets for therapeutic intervention, are needed. Peroxisome proliferator-activating receptor (PPAR)-? has been previously shown to be capable of regulating inflammatory responses in multiple organs. PPAR?-activating ligands, the thaizoladinediones (TZDs), are FDA approved. Regulation of PPAR? activity, using these drugs, is associated with reduced morbidity in animal models of inflammatory lung disease. However, the importance of this molecule in lung epithelial cells and in COPD has not been determined. We find increased expression of PPAR? in human COPD tissues, and in epithelial cells from smokers. In lung epithelial cells, PPAR? can regulate genes associated with lung tissue remodeling. We have previously reported that deficiency in PPAR? specifically within epithelial cells leads to a defect in lung maturation resulting in variation in lung structure and function in mice. Here, we present data indicating that mice deficient in lung epithelial cell PPAR? also show increased susceptibility to the development of emphysema in response to chronic cigarette smoke exposure. This is associated with an increase in the accumulation of inflammatory macrophages, the critical effector cell for emphysema pathogenesis, and increased lung chemokine gene expression. We present preliminary data indicating that activating PPAR? using TZDs in mice reduces smoke-related inflammation and chemokine expression, critical cellular and molecular intermediate phenotypes in this pre-clinical model of COPD. In vivo, epithelial cells are highly responsive to PPAR? regulators, and exposure to cigarette smoke increased PPAR? expression, supporting the contributions of epithelial cell PPAR? in regulating smoke-induced inflammation. In total, these data support a role for PPAR? as a susceptibility factor in COPD with potential as a target for disease-modifying therapy. We hypothesize that reduced PPAR? activity increases susceptibility to smoke- induced lung injury and that exogenous activation of PPAR? using TZDs will reduce COPD morbidity. We propose that epithelial PPAR? functions specifically to regulate the expression of epithelial-derived chemokines involved in inflammatory cell recruitment, macrophage activation and tissue destruction in response to chronic smoke exposure. In an effort to test these hypotheses we propose to: 1) Define the cellular and molecular mechanisms leading to increased susceptibility to cigarette smoke-induced emphysema in the absence of lung epithelial cell PPAR? function in mice. 2) Evaluate PPAR?-activating therapeutic ligands for the ability to limit emphysema pathology in mice exposed to cigarette smoke. 3) Investigate the ability of PPAR? activation to suppress smoke-induced lung epithelial cell chemokine expression in human cells and in COPD subjects as part of a phase II clinical trial. In total, these experiments will test the mechanistic role of PPAR? in a preclinical model of COPD, specifically address the role of epithelial cell PPAR? in regulating disease pathogenesis, and evaluate relevance and potential therapeutic benefits of PPAR? activation in humans with COPD.

描述(由申请人提供)：需要更好地理解导致COPD发病机制的机制，以及治疗干预的新靶点。过氧化物酶体增殖物激活受体-？此前已被证明有能力调节多个器官的炎症反应。PPAR？-激活配体，噻唑烷二酮(TZD)，已获得FDA批准。PPAR的调控？在炎症性肺部疾病的动物模型中，使用这些药物的活动与发病率的降低有关。然而，该分子在肺上皮细胞和COPD中的重要性尚未确定。我们发现PPAR？在人类COPD组织和吸烟者的上皮细胞中。在肺上皮细胞中，PPAR？可以调节与肺组织重塑相关的基因。我们之前已经报道过PPAR？尤其是在上皮细胞内，导致肺成熟缺陷，导致小鼠肺结构和功能的变化。在这里，我们提出的数据表明，肺上皮细胞PPAR？慢性香烟烟雾暴露也显示出对肺气肿发展的易感性增加。这与炎性巨噬细胞的聚集增加有关，炎性巨噬细胞是肺气肿发病的关键效应细胞，肺趋化因子基因表达增加。我们提供的初步数据表明，激活PPAR？在小鼠中使用TZDS可以减少吸烟相关的炎症和趋化因子的表达，这是COPD临床前模型中关键的细胞和分子中间表型。在体内，上皮细胞对PPAR？监管机构，以及接触香烟烟雾会增加PPAR吗？表达，支持上皮细胞PPAR的贡献？在调节烟雾引起的炎症方面。总而言之，这些数据支持PPAR的作用？作为COPD的易感因素，有可能成为疾病修正治疗的靶点。我们假设降低了PPAR？活性增加了对烟雾所致肺损伤的易感性，外源性PPAR？使用TZD将降低COPD的发病率。我们认为上皮性PPAR？其功能是专门调节上皮源性趋化因子的表达，这些趋化因子参与炎症细胞募集、巨噬细胞激活和组织破坏，以应对慢性烟雾暴露。为了验证这些假说，我们建议：1)确定在没有肺上皮细胞PPAR的情况下，导致香烟烟雾诱导的肺气肿易感性增加的细胞和分子机制？在小鼠身上起作用。2)评估PPAR？激活的治疗配体在香烟烟雾暴露的小鼠中限制肺气肿病理的能力。3)考察了PPAR？作为II期临床试验的一部分，激活以抑制吸烟诱导的人细胞和COPD受试者肺上皮细胞趋化因子的表达。总之，这些实验将检验PPAR？在COPD的临床前模型中，具体说明上皮细胞PPAR？在调节疾病的发病机制方面，以及评价PPAR的相关性和潜在的治疗益处？慢性阻塞性肺疾病患者体内的激活。