Biphasic alcohol regulation of TLR2 in airway epithelium

描述(由申请人提供)： 摘要/摘要：应聘者：我是一名肺部/重症监护内科医生，长期致力于成为一名内科科学家。我的短期目标是发展必要的技能，研究酒精对先天免疫的影响，酒精引起的表观遗传变化，以及酒精消费的体内模型。这些技能将为我提供必要的工具，在我的训练期结束时准备一份有竞争力的R-01。我的长期职业目标是通过促进对酒精引起的肺部天然免疫变化的理解，成为酒精研究领域的领导者。研究计划：我们将围绕确定酒精调节呼吸道上皮细胞Toll样受体2(TLR2)表达的机制这一目标来组织我的培训。TLR2是革兰氏阳性菌诱导的呼吸道炎症的重要调节因子。这种炎症反应导致呼吸道疾病，如支气管炎和慢性阻塞性肺疾病。我们发现，短暂的酒精暴露会导致TLR2的表达增加，而长时间的表达会导致TLR2的表达减少。我们将通过解决以下具体目标来确定酒精这种双相作用的机制：1)确定酒精调节RhoA活性的机制，以及这如何调节TLR2在呼吸道上皮细胞中的表达。2)表征酒精诱导的表观遗传学变化，这些变化导致TLR2的转录变化。3)确定酒精对TLR2的体内双向调节的功能意义。我需要额外的培训才能完成这些目标。具体地说，我将学习表观遗传学、细胞信号和统计学方面的课程。我将接受与表观遗传学研究相关的技术实践培训。我会参加与酒精有关的期刊俱乐部、会议和实验室会议。我还将出席国家和国际会议并介绍我的数据。环境：我选择的导师托德·怀亚特博士是一位公认的环核苷酸信号专家，并资助了酒精肺研究人员。此外，内布拉斯加大学医学中心有许多由NIAAA资助的研究人员，他们将在我的培训期间为我提供密集的指导。我的部门承诺了75%的受保护时间用于研究、技术人员、实验室和办公空间、启动资金和设备。公共卫生相关性：我们的长期目标是了解为什么酗酒者有更严重的肺部呼吸道疾病。更好地了解酒精是如何影响肺部炎症过程的，将有助于对酗酒者的呼吸道疾病进行更有针对性的治疗，并降低发病率和死亡率。 公共卫生相关性： 项目简介：我们的长期目标是了解为什么酗酒者有更严重的肺部呼吸道疾病。更好地了解酒精是如何影响肺部炎症过程的，将有助于对酗酒者的呼吸道疾病进行更有针对性的治疗，并降低发病率和死亡率。

DESCRIPTION (provided by applicant): ABSTRACT/SUMMARY: Candidate: I am a Pulmonary/Critical Care physician with a long-standing commitment to becoming a physician-scientist. My short-term goal is to develop the skills necessary to study alcohol's effect on innate immunity, epigenetic changes caused by alcohol and in vivo models of alcohol consumption. These skills will provide me with the tools necessary to prepare a competitive R-01 at the end of my training period. My long-term career goal is to become a leader in the field of alcohol research by advancing the understanding of alcohol-induced changes to the innate immunity of the lung. Research Plan: We will structure my training around the goal of determining the mechanisms through which alcohol modulates the expression of Toll-like receptor 2 (TLR2) in the airway epithelium. TLR2 is an important modulator of airway inflammation induced by gram-positive bacteria. This inflammatory response contributes to airway diseases such as bronchitis and chronic obstructive pulmonary disease. We have shown that brief alcohol exposure leads to an increase in the expression of TLR2, while prolonged expression leads to a decrease of TLR2. We will determine the mechanism of this biphasic effect of alcohol by addressing the following specific aims: 1) Determine the mechanism of alcohol's modulation of RhoA activity, and how this regulates TLR2 expression in the airway epithelium. 2) Characterize the alcohol-induced epigenetic changes that lead to transcriptional changes in TLR2. 3) Determine the functional significance of alcohol's biphasic modulation of TLR2 in vivo. I will require additional training to be able to complete these aims. Specifically, I will take courses in epigenetics, cell signaling and statistics. I will receive hands on training in techniques related to epigenetic studies. I will attend alcohol-related journal clubs, conferences and lab meetings. I will also attend and present my data at national and international meetings. Environment: My chosen Mentor, Dr. Todd Wyatt, is a recognized expert in cyclic nucleotide signaling and funded alcohol lung researcher. In addition, the University of Nebraska Medical Center has numerous NIAAA funded researchers who will provide intensive mentoring for me during my training period. My department has committed 75% protected time for research, a technician, laboratory and office space, start-up funds, and equipment. Public health relevance: Our long-term goal is to understand why alcoholics have more severe airway disease of the lung. A better understanding of how alcohol influences inflammatory processes in the lung will lead to more targeted therapy of airway disease in alcoholics and result in decreased morbidity and mortality. PUBLIC HEALTH RELEVANCE: Project Narrative: Our long-term goal is to understand why alcoholics have more severe airway disease of the lung. A better understanding of how alcohol influences inflammatory processes in the lung will lead to more targeted therapy of airway disease in alcoholics and result in decreased morbidity and mortality.