Biphasic alcohol regulation of TLR2 in airway epithelium

摘要/摘要 应聘者：我是一名肺部/重症监护医生，长期致力于成为 医生兼科学家。我的短期目标是发展必要的技能来研究酒精对先天的影响 免疫、酒精引起的表观遗传变化和酒精消费的体内模型。这些技能将 为我提供必要的工具，以便在我的训练期结束时准备一份有竞争力的R-01。我的龙- 学期的职业目标是通过促进对酒精研究的理解，成为酒精研究领域的领导者 酒精引起的肺部先天免疫功能的改变。 研究计划：我们将围绕确定以下机制的目标来构建我的培训 酒精对呼吸道上皮细胞Toll样受体2(TLR2)表达的调节作用TLR2是一个重要的 革兰氏阳性菌所致呼吸道炎症的调节因子。这种炎症反应有助于 呼吸道疾病，如支气管炎和慢性阻塞性肺疾病。我们已经展示了这份简报 酒精暴露导致TLR2表达增加，而长时间表达则导致 TLR2降低。我们将通过解决以下问题来确定酒精这种双相效应的机制 具体目标如下：1)确定酒精对RhoA活性的调节机制，以及这是如何实现的 调节TLR2在呼吸道上皮细胞中的表达。2)描述酒精引起的表观遗传学变化 这会导致TLR2的转录变化。3)确定酒精两相的功能意义 TLR2在体内的调控。我需要额外的培训才能完成这些目标。具体来说，我 将学习表观遗传学、细胞信号和统计学方面的课程。我将接受技术方面的实践培训 与表观遗传学研究有关。我会参加与酒精有关的期刊俱乐部、会议和实验室会议。这就做 我还参加国家和国际会议，并在会上介绍我的数据。 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和 资助酒精肺病研究人员。此外，内布拉斯加大学医学中心有许多NIAAA 资助研究人员，他们将在我的培训期间为我提供密集的指导。我的部门已经 承诺75%的受保护时间用于研究、技术人员、实验室和办公空间、启动资金以及 设备。 与公共健康相关：我们的长期目标是了解为什么酗酒者的呼吸道更严重 肺部疾病。更好地了解酒精如何影响肺部的炎症过程将 导致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。

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.