Effect of PPAR?? Ligands on Alcohol-Induced Alveolar Macrophage Dysfunction

PPAR的作用??

• 批准号: 8203027
• 负责人: Samantha M. Yeligar
• 金额: $ 4.84万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-30 至 2012-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8203027
• 关键词: 2,4-thiazolidinedione; Adult Respiratory Distress Syndrome; Affect; Alcohol abuse; Alcohols; Alveolar Cell; Alveolar Macrophages; Apoptotic; Applications Grants; Arachidonate 5-Lipoxygenase; Attenuated; Biology; Biomedical Research; Bronchitis; Cell Line; Chronic; Data; Disease; Down-Regulation; Endothelial Cells; Endothelin-1; Ethanol; Exhibits; Fatty Liver; Functional disorder; Funding; Future; Goals; Grant; Immune response; In Vitro; Infection; Inflammation; Investigation; Knockout Mice; Kupffer Cells; Laboratories; Ligands; Liver; Liver Cirrhosis; Lung; Macrophage Activation; Manuscripts; Mediating; Mentorship; MicroRNAs; Microbe; Modeling; Molecular Biology Techniques; Mus; National Research Service Awards; Non-Insulin-Dependent Diabetes Mellitus; Oxidative Stress; PPAR gamma; Patients; Peroxisome Proliferator-Activated Receptors; Phagocytosis; Pharmaceutical Preparations; Pioglitazone; Pneumonia; Predisposition; Preparation; Proteins; Rattus; Recording of previous events; Research; Research Personnel; Resources; Respiratory Burst; Respiratory Tract Infections; Risk; Scientist; Secondary to; Series; Signal Transduction; Surface; Therapeutic; Thiazolidinediones; Tissues; Transforming Growth Factor beta; Transgenic Mice; Universities; Up-Regulation; Writing; alcohol effect; alcohol exposure; base; career; chronic alcohol ingestion; experience; feeding; graduate student; human TGFB1 protein; hypoxia inducible factor 1; improved; in vivo Model; insulin sensitivity; lung injury; macrophage; meetings; mouse model; novel; novel therapeutic intervention; particle; problem drinker; receptor; receptor expression; research study; response; rosiglitazone; skills

DESCRIPTION (provided by applicant): Chronic alcohol abuse increases patients' risk of developing Acute Respiratory Distress Syndrome (ARDS) and respiratory infections. In the lung, chronic alcohol ingestion reduces peroxisome proliferator- activated receptor gamma (PPARg) levels and increases transforming growth factor beta-1 (TGF21) expression, leading to alveolar macrophage (AM) alternative activation and dysfunction. These alcohol- induced derangements can be reversed by treatment with PPARg ligands, such as pioglitazone and rosiglitazone. The studies outlined in this proposal will examine the effect of alcohol on AM PPARg expression and activity as modulated by microRNAs (Aim 1). Then, we will determine the capacity of PPARg ligands to reverse alcohol-mediated AM dysfunction (Aim 2). These hypotheses will be investigated by performing various experiments on a murine model of chronic alcohol consumption and an in vitro ethanol exposed mouse AM cell line, MH-S. We will evaluate whether chronic alcohol exposure compromises PPARg signaling in AMs, how ethanol-induced alterations in microRNAs modulate PPARg, and whether treatment with PPARg ligands can upregulate ethanol-mediated reductions in AM PPARg. Further, we will determine whether PPARg ligands can attenuate ethanol-induced AM TGF21, alternative activation and dysfunction. The studies outlined in this proposal will demonstrate that treatment with PPARg ligands has potential to identify a novel therapeutic approach to ameliorating alcohol-mediated AM dysfunction and associated susceptibility to lung injury and infection. If successful, this line of investigation could have considerable translational impact on the management of patients with alcohol abuse disorders. With support from this NRSA grant, mentorship by well-established researchers, and opportunities and resources available at Emory University's Alcohol and Lung Biology Center, the next one year will be used to hone my molecular biology techniques by attending courses offered at Emory University, collect critical preliminary data for subsequent K-series grant applications, present research findings at national meetings, and gain experience in manuscript writing and grant preparation, with the ultimate goal of progressing towards a career as an independent scientist in biomedical research. PUBLIC HEALTH RELEVANCE: Alcoholics have an increased risk of developing respiratory infections, such as bronchitis and pneumonia, due to impaired function of alveolar macrophages to clear infectious particles. PPARg receptor ligands, which include synthetic thiazolidinedione (TZD) medications such as pioglitazone and rosiglitazone, have been found to reduce chronic alcohol-induced hepatic steatosis and inflammation involving Kupffer cells. The studies outlined in this proposal will determine whether PPARg ligand treatment can upregulate PPARg to improve alcohol-induced alveolar macrophage dysfunction and be a novel therapy in reducing respiratory infections among patients with a history of alcohol abuse.

描述（由申请人提供）：长期酗酒会增加患者患急性呼吸窘迫综合征（ARDS）和呼吸道感染的风险。在肺部，长期饮酒会降低过氧化物酶体增殖物激活受体γ（PPARg）水平并增加转化生长因子β-1（TGF21）表达，导致肺泡巨噬细胞（AM）替代激活和功能障碍。这些酒精引起的紊乱可以通过 PPARg 配体（例如吡格列酮和罗格列酮）治疗来逆转。该提案中概述的研究将检查酒精对 microRNA 调节的 AM PPARg 表达和活性的影响（目标 1）。然后，我们将确定 PPARg 配体逆转酒精介导的 AM 功能障碍的能力（目标 2）。这些假设将通过对长期饮酒的小鼠模型和体外乙醇暴露的小鼠 AM 细胞系 MH-S 进行各种实验来研究。我们将评估长期酒精暴露是否会损害 AM 中的 PPARg 信号传导，乙醇诱导的 microRNA 改变如何调节 PPARg，以及 PPARg 配体治疗是否可以上调乙醇介导的 AM PPARg 减少。此外，我们将确定 PPARg 配体是否可以减弱乙醇诱导的 AM TGF21、选择性激活和功能障碍。该提案中概述的研究将证明，PPARg 配体治疗有可能确定一种新的治疗方法，以改善酒精介导的 AM 功能障碍以及相关的肺损伤和感染易感性。如果成功，这一研究方向可能会对酒精滥用障碍患者的治疗产生相当大的转化影响。在 NRSA 拨款的支持、知名研究人员的指导以及埃默里大学酒精和肺生物学中心提供的机会和资源的支持下，接下来的一年将通过参加埃默里大学提供的课程来磨练我的分子生物学技术，收集为后续 K 系列资助申请提供关键的初步数据，在全国会议上展示研究成果，并获得手稿写作和资助准备的经验，最终目标是成为生物医学研究的独立科学家。 公共卫生相关性：由于肺泡巨噬细胞清除传染性颗粒的功能受损，酗酒者患呼吸道感染（例如支气管炎和肺炎）的风险增加。 PPARg 受体配体，包括吡格列酮和罗格列酮等合成噻唑烷二酮 (TZD) 药物，已被发现可以减少慢性酒精引起的肝脂肪变性和涉及库普弗细胞的炎症。该提案中概述的研究将确定 PPARg 配体治疗是否可以上调 PPARg 以改善酒精引起的肺泡巨噬细胞功能障碍，并成为减少有酒精滥用史的患者呼吸道感染的新疗法。