Biphasic alcohol regulation of TLR2 in airway epithelium

气道上皮 TLR2 的双相酒精调节

• 批准号: 8436337
• 负责人: Kristina L Bailey
• 金额: $ 17.86万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8436337
• 关键词: Acute; Address; Affect; Air; Alcohol consumption; Alcohols; Animal Model; Binding; Bronchitis; Cell Wall; Chronic; Chronic Bronchitis; Chronic Obstructive Airway Disease; Commit; Critical Care; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Cyclic Nucleotides; DNA Methylation; Data; Disease; Down-Regulation; Effector Cell; Environment; Epigenetic Process; Epithelial Cells; Epithelium; Equipment; Funding; Gene Expression Regulation; Genetic Transcription; Goals; Gram-Positive Bacteria; Hand; Histone Acetylation; IL8 gene; Immune; Immune system; Inflammation; Inflammatory; Inflammatory Response; International; Journals; Laboratories; Laboratory Technicians; Lead; Learning; Ligands; Lung; Lung diseases; Medical center; Mentors; Modification; Molecular; Monomeric GTP-Binding Proteins; Morbidity - disease rate; Motion; Mus; National Institute on Alcohol Abuse and Alcoholism; Natural Immunity; Nebraska; Neutrophil Infiltration; Nitric Oxide; Pathway interactions; Physicians; Play; Process; Promoter Regions; Regulation; Research; Research Personnel; Role; Scientist; Signal Transduction; Staphylococcus aureus; Streptococcus pneumoniae; Structure; Techniques; Testing; Time; Tissues; Toll-Like Receptor 2; Training; Transcriptional Regulation; Universities; Up-Regulation; Vascular Endothelium; Work; airway epithelium; airway inflammation; alcohol effect; alcohol exposure; alcohol research; career; cytokine; feeding; in vivo; in vivo Model; macrophage; meetings; monocyte; mortality; novel; pathogen; problem drinker; public health relevance; respiratory; response; skills; statistics; symposium; tool

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.

摘要/摘要 候选人：我是肺部/重症监护医师，长期以来一直致力于成为 医师科学家。我的短期目标是发展研究酒精对先天作用所需的技能 免疫力，饮酒引起的表观遗传变化和饮酒的体内模型。这些技能会 为我提供在培训期结束时准备竞争性R-01所需的工具。我的长期 任期职业目标是通过促进对酒精研究领域的领导者的理解 酒精引起的肺部先天免疫变化。 研究计划：我们将围绕确定通过哪种机制的目标进行培训 酒精调节气道上皮中的Toll样受体2（TLR2）的表达。 TLR2很重要 革兰氏阳性细菌引起的气道炎症调节剂。这种炎症反应有助于 气道疾病，例如支气管炎和慢性阻塞性肺部疾病。我们已经证明了简短的 酒精暴露导致TLR2的表达增加，而延长的表达导致 减少TLR2。我们将通过解决该酒精的双相作用的机制 以下特定目的：1）确定酒精对RhoA活性调节的机制，以及如何 调节气道上皮中的TLR2表达。 2）表征酒精引起的表观遗传变化 这导致TLR2的转录变化。 3）确定酒精双相的功能意义 TLR2在体内的调节。我将需要额外的培训才能完成这些目标。具体来说，我 将参加表观遗传学，细胞信号传导和统计的课程。我将获得技巧培训 与表观遗传学研究有关。我将参加与酒精有关的期刊俱乐部，会议和实验室会议。我会 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（Todd Wyatt）博士是循环核苷酸信号传导和 资助的酒精肺研究员。此外，内布拉斯加州大学医学中心有许多NIAAA 资助的研究人员将在我的培训期间为我提供密集的指导。我的部门有 提出了75％的研究时间，技术人员，实验室和办公空间，初创企业资金以及 设备。