Biphasic alcohol regulation of TLR2 in airway epithelium

摘要/总结 候选人：我是一名肺部/重症监护医生，长期致力于成为一名 物理学家兼科学家我的短期目标是发展必要的技能，研究酒精对先天性心脏病的影响。 免疫、酒精引起的表观遗传变化和酒精消耗的体内模型。这些技能将 为我提供必要的工具，在我的培训期结束时准备一个有竞争力的R-01。我的长- 长期的职业目标是通过提高对酒精研究领域的理解， 酒精引起的肺部先天免疫的变化。 研究计划：我们将围绕确定机制的目标来构建我的培训， 酒精调节气道上皮中Toll样受体2（TLR 2）的表达。TLR 2是一种重要的 革兰氏阳性菌诱导的气道炎症调节剂。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病。我们已经证明了这一简短的 酒精暴露导致TLR 2表达增加，而长期表达导致TLR 2表达增加。 TLR 2的降低我们将通过解决酒精的双相效应来确定其机制。 具体目的如下：1）确定酒精对RhoA活性的调节机制，以及这种调节机制如何影响RhoA的活性。 调节气道上皮中TLR 2的表达。2)描述酒精引起的表观遗传变化 导致TLR 2的转录变化。3)确定酒精双相的功能意义 TLR 2在体内的调节。我需要额外的培训才能完成这些目标。我特别 将学习表观遗传学、细胞信号和统计学等课程。我将接受技术培训 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。我会 我还参加并在国家和国际会议上介绍我的数据。 环境：我选择的导师，托德怀亚特博士，是一个公认的专家在环核苷酸信号， 资助的酒精肺病研究员此外，内布拉斯加大学医学中心有许多NIAAA 他们将在我的培训期间为我提供密集的指导。律政司 承诺75%的保护时间用于研究、技术人员、实验室和办公空间、启动资金， 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呼吸道疾病。 肺部疾病。更好地了解酒精如何影响肺部炎症过程， 从而导致对酗酒者气道疾病更有针对性的治疗，并导致发病率和死亡率的降低。

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.