Alcohol, Pulmonary Cytokines, and Host Defense

酒精、肺细胞因子和宿主防御

• 批准号: 7089049
• 负责人: KYLE I HAPPEL
• 金额: $ 17.22万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-20 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7089049
• 关键词: Klebsiella pneumoniae; SDS polyacrylamide gel electrophoresis; alcoholic beverage consumption; alcoholism /alcohol abuse; alveolar macrophages; bacteria infection mechanism; biological signal transduction; cytokine; cytokine receptors; diagnostic respiratory lavage; flow cytometry; fluorescence resonance energy transfer; gel mobility shift assay; host organism interaction; immunity; immunosuppression; interferon gamma; interleukin 10; laboratory mouse; lung disorder; nuclear factor kappa beta; polymerase chain reaction; receptor expression; respiratory infections; tissue /cell culture

DESCRIPTION (provided by applicant): Our proposal details a 5-year training program designed to facilitate development of the applicant into an independent clinician research scientist with expertise in alcohol's effects on pulmonary host defenses. Having completed his fellowship in Pulmonary and Critical Care Medicine, the applicant will join the LSU faculty as an assistant professor in January 2004. He is now finishing post-doctoral training in the basic research facilities of the LSU Alcohol Research Center, where his current focus involves alcohol's effect on the development of a coordinated host defense response to bacterial pneumonia. Through inhibition of cytokines such as IL-12 which functionally link innate and adaptive immunity, alcohol intoxication worsens the outcome from bacterial pneumonia, increasing patient morbidity and mortality. IL-23 and IL-27 are recently identified cytokines similar to, but distinct from, IL-12 in their roles as soluble messengers between cellular components of innate and adaptive immunity. This research proposal is focused on novel mechanisms through which alcohol intoxication can disrupt the normal interface between innate and adaptive immune responses to bacterial infection in the lung. Specifically, alcohol's effect on IL-23 and IL-27 expression during pulmonary infection with Klebsiella pneumoniae will be studied. Our specific aims will address: 1) the in vivo and in vitro ability of alcohol to suppress pulmonary IL-23/IL-27 gene and protein expression during K. pneumoniae infection 2) the relationship between alcohol's effects on IL-23/IL-27 and its modulation of a) NF-KappaB and b) IL-10 expression during infection 3) the ability of recombinant interferongamma to attenuate alcohol's effects on IL-23 and IL-27 in response to K. pneumoniae and 4) the ability of locally delivered IL-23 or IL-27 gene therapy to improve the outcome of pulmonary infection with K. pneumoniae during alcohol intoxication. This work entails novel basic research which will also serve as a vehicle through which the applicant will learn specific techniques of alcohol modeling, bacteriology, immunology, molecular biology, and gene therapy. As such, these experiments will be performed in the highly productive environment of the LSU Alcohol Research Center laboratories. The didactic program and basic research experiences in this mentored proposal are designed to catalyze the applicant's development into an independent investigator in the field of alcoholism and pulmonary host defenses.

描述（由申请人提供）：我们的提案详细介绍了一项为期5年的培训计划，旨在促进申请人发展为独立的临床研究科学家，在酒精对肺部宿主防御的影响方面具有专业知识。 申请人完成了肺和重症监护医学的研究金后，申请人将于2004年1月加入LSU教师担任助理教授。他现在正在LSU酒精研究中心的基础研究设施中完成博士后培训涉及酒精对宿主对细菌肺炎的协调防御反应的影响。 通过抑制细胞因子，例如IL-12，在功能上将先天性和适应性免疫联系起来，酒精中毒会使细菌性肺炎的结果恶化，从而增加了患者的发病率和死亡率。 最近发现IL-23和IL-27的细胞因子与IL-12相似，但与IL-12的作用不同，它们是先天性和适应性免疫的细胞成分之间的可溶性使者。该研究建议的重点是新的机制，通过这些机制，酒精中毒可以破坏对肺中细菌感染的先天和适应性免疫反应之间的正常界面。 具体而言，将研究肺炎肺炎肺部感染过程中酒精对IL-23和IL-27表达的影响。我们的具体目的将解决：1）酒精抑制肺IL-23/IL-27基因的体内和体外能力和肺炎感染期间蛋白质表达2）酒精对IL-23/IL-的影响之间的关系27及其对a）NF-kappab和b）感染期间的IL-10表达的调节3）重组干扰素对肺炎的IL-23和IL-27的影响减弱酒精对肺炎和4）的能力的能力局部递送的IL-23或IL-27基因治疗，以改善酒精中毒期间肺炎肺炎的肺部感染结果。这项工作需要新颖的基础研究，该研究还将用作申请人的媒介，将学习酒精建模，细菌学，免疫学，分子生物学和基因治疗的特定技术。 因此，这些实验将在LSU酒精研究中心实验室的高产环境中进行。该指导提案中的教学计划和基础研究经验旨在将申请人的发展催化为酒精中毒和肺部宿主防御领域的独立研究者。