The host mucosal response to microbial iron metabolism

描述(由申请人提供)：这份建议书描述了一项为期5年的培训计划，旨在发展临床病理学和微生物学的学术生涯。这项拟议的研究将调查粘膜对细菌铁代谢的炎症反应。为了应对不同的细菌，呼吸道粘膜会分泌铁胆碱(Lipocalin2)，这是一种与细菌铁清除分子Enterobactin结合的小蛋白。西德罗卡林将铁从细菌中隔离出来，并可以防止依赖肠杆菌素的细菌复制。在细胞培养中，1铁胆碱与肠杆菌素结合会导致趋化因子IL-8的释放，这表明它有额外的促炎作用。这项研究计划将通过以下目的来验证基于其结合的肠结合蛋白的铁状态而介导粘膜炎症反应的假说：1)确定在体内是否铁胆碱介导了对细菌的粘膜炎症反应。PI将使用鼻部定植和肺炎的动物模型、铁胆碱基因敲除小鼠和同基因肺炎克雷伯菌肠杆菌突变株来测量铁胆碱对细菌生长、趋化因子产生和中性粒细胞再生的影响。2)确定体外释放趋化因子所需的细胞成分。PI将使用细胞培养模型来确定铁胆碱受体和趋化因子调节蛋白对铁胆碱的反应需求。首席研究员迈克尔·巴赫曼医学博士已经完成了他在宾夕法尼亚大学医院的临床病理学实习。他正在扩展他的研究技能，包括对细菌病原体的先天免疫力，并将他的职业生涯集中在医学微生物学上。他的顾问是杰弗里·威瑟医学博士，他是宿主对细菌定植反应的专家。为了利用更多的专业知识，他成立了一个科学咨询委员会，由罗伯特·威尔逊医学博士(人体铁代谢)、大卫·阿蒂斯博士(粘膜免疫学)和迈克尔·梅(信号转导)组成。宾夕法尼亚大学的师资和设施使其成为完成这一培训计划的理想环境。与公共卫生相关：我们的粘膜为细菌感染提供了第一道屏障，这是一种至关重要的功能，对免疫功能低下和危重患者尤其重要，本提案将研究抑制细菌生长的铁锈菌蛋白。通过了解铁胆碱的作用机制，我们有可能开发新的治疗方法来增强粘膜免疫或抑制细菌策略来阻碍粘膜免疫。

DESCRIPTION (provided by applicant): This proposal describes a 5-year training program to develop an academic career in Clinical Pathology and Microbiology. The proposed research will investigate the mucosal inflammatory response to bacterial iron metabolism. In response to diverse bacteria, the respiratory mucosa secretes siderocalin (lipocalin2), a small protein that binds the bacterial iron scavenging molecule enterobactin. Siderocalin sequesters iron from bacteria, and can prevent replication of enterobactin-dependent bacteria. In cell culture,1 siderocalin bound to enterobactin causes release of the chemokine IL-8, suggesting it has additional pro-inflammatory effects. This research plan will test the hypothesis that siderocalin mediates a mucosal inflammatory response, based on the iron-status of its bound enterobactin, through the followingaims: 1) Determine if siderocalin mediates a mucosal inflammatory response to bacteria in vivo. The PI will use animal models of nasal colonization and pneumonia,siderocalin knockout mice and isogenic Klebisiella pneumoniae enterobactin mutants to measure the effects of siderocalin on bacterial growth, chemokine production and neutrophil recriutment. 2) Identify the cellular components required for chemokine release in response to siderocalin in vitro. The PI will use a cell culture model to determine the requirement for the siderocalin receptor and chemokine regulatory proteins to respond to siderocalin. The principal investigator, Michael Bachman M.D. Ph.D., has completed his residency in Clinical Pathology at the Hospital of the Universityof Pennsylvania. He is expanding his reseach skills to include innate immunity to bacterial pathogens and focusing his career on medical microbiology. His advisor is Jeffrey Weiser M.D., an expert in the host response to bacterial colonization. To harness additional expertise, he has established a scientific advisory committee composed of Robert Wilson M.D. Ph.D.(human iron metabolism), David Artis Ph.D. (mucosal immunity) and Michael May (signal transduction). The faculty and facilities make the University of Pennsylvania an ideal environment in which to complete this training program. PUBLIC HEALTH RELEVANCE: Our mucosal membranes provide the first barrier to bacterial infection, a crucial function especially important in immunocompromised and critically ill patients, and this proposal will study the protein siderocalin that inhibits bacterial growth. By understanding the mechanism of siderocalin function, we can potentially develop novel therapeutics to enhance mucosal immunity or inhibit bacterial strategies that thwart it.