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

描述（由申请人提供）：慢性酒精滥用会增加患者发生急性呼吸窘迫综合征（ARDS）和呼吸道感染的风险。在肺部，慢性酒精摄入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配体治疗逆转，如吡格列酮和罗格列酮。本提案中概述的研究将检查酒精对微rna调节的AM PPARg表达和活性的影响（目的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（目的2）。这些假设将通过在小鼠慢性酒精消耗模型和体外乙醇暴露小鼠AM细胞系MH-S上进行各种实验来研究。我们将评估慢性酒精暴露是否会损害AM中的PPARg信号，乙醇诱导的微小rna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中PPARg的减少。此外，我们将确定PPARg配体是否可以减弱乙醇诱导的AM TGF21、替代激活和功能障碍。本提案中概述的研究将证明，用PPARg配体治疗有可能确定一种新的治疗方法来改善酒精介导的AM功能障碍和相关的肺损伤和感染易感性。如果成功，这条研究路线可能对酒精滥用障碍患者的管理产生相当大的转化影响。在NRSA基金的支持下，在知名研究人员的指导下，以及埃默里大学酒精和肺部生物学中心的机会和资源，接下来的一年，我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，为随后的k系列资助申请收集关键的初步数据，在全国会议上展示研究成果，并获得撰写手稿和准备资助的经验。最终目标是在生物医学研究领域成为一名独立的科学家。

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.