The host mucosal response to microbial iron metabolism

描述（由申请人提供）：本提案描述了一个为期5年的培训计划，以发展临床病理学和微生物学的学术生涯。这项研究将探讨粘膜炎症对细菌铁代谢的反应。呼吸道粘膜对不同细菌的反应是分泌铁运载蛋白（脂运载蛋白2），这是一种结合细菌铁清除分子肠杆菌素的小蛋白。Siderocalin从细菌中螯合铁，并且可以防止肠杆菌素依赖性细菌的复制。在细胞培养中，与肠杆菌素结合的1铁黄素引起趋化因子IL-8的释放，表明其具有额外的促炎作用。本研究计划基于铁代菌素结合肠杆菌素的铁状态，通过以下目的来检验铁代菌素介导粘膜炎症反应的假设：1）确定铁代菌素是否介导体内对细菌的粘膜炎症反应。PI将使用鼻定植和肺炎的动物模型、铁黄素敲除小鼠和等基因肺炎克雷伯菌肠杆菌素突变体来测量铁黄素对细菌生长、趋化因子产生和中性粒细胞再融合的影响。2)鉴定体外铁载体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对铁黄素受体和趋化因子调节蛋白的需求，以响应铁黄素。首席研究员迈克尔·巴赫曼医学博士博士，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，并将他的职业生涯集中在医学微生物学上。他的导师是杰弗里·韦瑟医学博士，研究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·威尔逊医学博士组成。博士（人体铁代谢），大卫阿蒂斯博士。（粘膜免疫）和Michael May（信号转导）。教师和设施使宾夕法尼亚大学成为完成该培训计划的理想环境。公共卫生相关性：我们的粘膜提供了细菌感染的第一道屏障，这是一个至关重要的功能，在免疫功能低下和重症患者中尤其重要，这项提案将研究抑制细菌生长的铁黄素蛋白。通过了解铁黄素功能的机制，我们可以潜在地开发新的治疗方法来增强粘膜免疫力或抑制阻碍它的细菌策略。

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.