PPAR gamma as a therapeutic target in COPD

PPAR γ 作为 COPD 的治疗靶点

• 批准号: 8644852
• 负责人: THOMAS J MARIANI
• 金额: $ 37.46万
• 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 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8644852
• 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; 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; Receptor Activation; Receptor Gene; 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; genetic variant; 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; receptor expression; receptor function; 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）：需要加深对导致 COPD 发病机制的理解，以及治疗干预的新目标。过氧化物酶体增殖物激活受体（PPAR）-？先前已被证明能够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 的调节？使用这些药物的活动与炎症性肺病动物模型的发病率降低有关。然而，该分子在肺上皮细胞和慢性阻塞性肺病中的重要性尚未确定。我们发现 PPAR 表达增加？在人类慢性阻塞性肺病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。我们之前曾报道过PPAR缺乏？特别是在上皮细胞内，会导致肺成熟缺陷，从而导致小鼠肺结构和功能的变化。在这里，我们提供的数据表明小鼠肺上皮细胞 PPAR 缺乏？还显示出因长期接触香烟烟雾而发生肺气肿的易感性增加。这与炎症巨噬细胞（肺气肿发病机制的关键效应细胞）积累的增加以及肺趋化因子基因表达的增加有关。我们提供的初步数据表明激活 PPAR？在小鼠中使用 TZD 可减少与烟雾相关的炎症和趋化因子表达，以及 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 PPAR 高度敏感？调节剂和暴露于香烟烟雾会增加 PPAR 吗？表达，支持上皮细胞 PPAR 的贡献？调节烟雾引起的炎症。总的来说，这些数据支持 PPAR 的作用吗？作为 COPD 的易感因素，有可能成为疾病缓解治疗的目标。我们假设 PPAR 降低了？活性增加了对烟雾引起的肺损伤的易感性，并且 PPAR 的外源性激活？使用 TZD 会降低 COPD 发病率。我们提出上皮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、巨噬细胞激活和慢性烟雾暴露引起的组织破坏。为了检验这些假设，我们建议：1）定义在缺乏肺上皮细胞 PPAR 的情况下导致对香烟烟雾诱发的肺气肿的易感性增加的细胞和分子机制？在小鼠中发挥作用。 2) 评估 PPAR 激活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）考察PPAR的能力？作为 II 期临床试验的一部分，激活抑制人类细胞和 COPD 受试者中烟雾诱导的肺上皮细胞趋化因子表达。总的来说，这些实验将测试 PPAR 的机制作用？在 COPD 的临床前模型中，具体解决上皮细胞 PPAR 的作用？调节疾病发病机制，并评估 PPAR 的相关性和潜在治疗益处？患有慢性阻塞性肺病 (COPD) 的人中的激活。