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成为一名独立的临床研究科学家，拥有酒精对肺部宿主防御影响的专业知识。 完成肺科和重症监护医学专科培训后，申请人将于 2004 年 1 月加入路易斯安那州立大学，担任助理教授。他目前正在路易斯安那州立大学酒精研究中心的基础研究设施中完成博士后培训，他目前的研究重点是该中心涉及酒精对宿主对细菌性肺炎的协调防御反应的影响。 通过抑制IL-12等细胞因子（其功能是连接先天免疫和适应性免疫），酒精中毒会恶化细菌性肺炎的结果，增加患者的发病率和死亡率。 最近发现 IL-23 和 IL-27 是与 IL-12 相似但又不同的细胞因子，它们作为先天性免疫和适应性免疫的细胞成分之间的可溶性信使的作用。这项研究计划的重点是酒精中毒可以破坏肺部细菌感染的先天免疫反应和适应性免疫反应之间的正常界面的新机制。 具体而言，将研究肺炎克雷伯菌肺部感染期间酒精对 IL-23 和 IL-27 表达的影响。我们的具体目标将解决：1) 酒精在肺炎克雷伯菌感染期间抑制肺部 IL-23/IL-27 基因和蛋白表达的体内和体外能力 2) 酒精对 IL-23/IL-27 影响之间的关系27 及其在感染期间对 a) NF-KappaB 和 b) IL-10 表达的调节 3) 重组干扰素伽马减弱酒精对 IL-23 和 IL-27 的影响的能力肺炎克雷伯菌和 4) 局部递送的 IL-23 或 IL-27 基因治疗改善酒精中毒期间肺炎克雷伯菌肺部感染结果的能力。这项工作需要新颖的基础研究，也将作为申请人学习酒精建模、细菌学、免疫学、分子生物学和基因治疗的具体技术的工具。 因此，这些实验将在路易斯安那州立大学酒精研究中心实验室的高生产力环境中进行。本指导提案中的教学计划和基础研究经验旨在促进申请人发展成为酗酒和肺部宿主防御领域的独立研究者。