PPAR gamma as a therapeutic target in COPD

PPAR γ 作为 COPD 的治疗靶点

• 批准号: 8270472
• 负责人: THOMAS J MARIANI
• 金额: $ 39.34万
• 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/8270472
• 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 Delivery Systems; 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)-y has been previously shown to be capable of regulating inflammatory responses in multiple organs. PPARy-activating ligands, the thaizoladinediones (TZDs), are FDA approved. Regulation of PPARy 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 PPARy in human COPD tissues, and in epithelial cells from smokers. In lung epithelial cells, PPARy can regulate genes associated with lung tissue remodeling. We have previously reported that deficiency in PPARy 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 PPARy 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 PPARy 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 PPARy regulators, and exposure to cigarette smoke increased PPARy expression, supporting the contributions of epithelial cell PPARy in regulating smoke-induced inflammation. In total, these data support a role for PPARy as a susceptibility factor in COPD with potential as a target for disease-modifying therapy. We hypothesize that reduced PPARy activity increases susceptibility to smoke- induced lung injury and that exogenous activation of PPARy using TZDs will reduce COPD morbidity. We propose that epithelial PPARy 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 PPARy function in mice. 2) Evaluate PPARy-activating therapeutic ligands for the ability to limit emphysema pathology in mice exposed to cigarette smoke. 3) Investigate the ability of PPARy 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 PPARy in a preclinical model of COPD, specifically address the role of epithelial cell PPARy in regulating disease pathogenesis, and evaluate relevance and potential therapeutic benefits of PPARy 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（PPAR）-γ先前已被证明能够调节多个器官中的炎症反应。PPARy激活配体thaizoladinediones（TZD）已获得FDA批准。使用这些药物调节PPARy活性与炎性肺病动物模型中发病率降低相关。然而，这种分子在肺上皮细胞和COPD中的重要性尚未确定。我们发现在人COPD组织和吸烟者的上皮细胞中PPARy的表达增加。在肺上皮细胞中，PPARy可以调节与肺组织重塑相关的基因。我们以前曾报道过，特异性地在上皮细胞内缺乏PPARy导致肺成熟缺陷，导致小鼠肺结构和功能的变化。在此，我们提供的数据表明，肺上皮细胞PPARy缺陷的小鼠也表现出对慢性香烟烟雾暴露的肺气肿发展的易感性增加。这与炎性巨噬细胞（肺气肿发病机制的关键效应细胞）的积累增加和肺趋化因子基因表达增加有关。我们提出的初步数据表明，在小鼠中使用TZD激活PPARy减少了吸烟相关的炎症和趋化因子表达，这是COPD临床前模型中的关键细胞和分子中间表型。在体内，上皮细胞对PPARy调节剂高度响应，并且暴露于香烟烟雾增加PPARy表达，支持上皮细胞PPARy在调节烟雾诱导的炎症中的贡献。总之，这些数据支持PPARy作为COPD中的易感性因子的作用，其具有作为疾病改善治疗的靶点的潜力。我们假设降低的PPARy活性增加对烟雾诱导的肺损伤的易感性，并且使用TZD外源性激活PPARy将降低COPD发病率。我们提出，上皮细胞的PPARy功能特异性地调节上皮细胞衍生的趋化因子的表达，这些趋化因子参与慢性烟雾暴露引起的炎性细胞募集、巨噬细胞活化和组织破坏。为了检验这些假设，我们提出：1）定义在小鼠中在肺上皮细胞PPARy功能不存在的情况下导致对香烟烟雾诱导的肺气肿的易感性增加的细胞和分子机制。2)评价PPARy活化治疗配体限制暴露于香烟烟雾的小鼠肺气肿病理学的能力。3)作为II期临床试验的一部分，研究PPARy活化抑制人细胞和COPD受试者中烟雾诱导的肺上皮细胞趋化因子表达的能力。总之，这些实验将测试PPARy在COPD的临床前模型中的机制作用，特别是解决上皮细胞PPARy在调节疾病发病机制中的作用，并评估PPARy活化在患有COPD的人中的相关性和潜在治疗益处。