The host mucosal response to microbial iron metabolism

描述（由申请人提供）：该提案描述了一个为期 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。拟议的研究将调查细菌铁代谢的粘膜炎症反应。为了应对不同的细菌，呼吸道粘膜会分泌铁运载蛋白（lipocalin2），这是一种与细菌铁清除分子肠杆菌素结合的小蛋白质。铁运载蛋白可将铁与细菌隔离，并可防止依赖肠杆菌素的细菌的复制。在细胞培养中，1铁蛋白与肠杆菌素结合会导致趋化因子 IL-8 的释放，表明它具有额外的促炎作用。该研究计划将根据其结合的肠杆菌素的铁状态，通过以下目标来检验铁铁蛋白介导粘膜炎症反应的假设：1）确定铁铁蛋白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动物模型、铁铁蛋白敲除小鼠和同基因肺炎克雷比氏菌肠杆菌素突变体来测量铁铁蛋白对细菌生长、趋化因子产生和中性粒细胞招募的影响。 2) 确定体外响应铁运蛋白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铁蛋白受体和趋化因子调节蛋白响应铁铁蛋白的需要。主要研究者 Michael Bachman 医学博士已在宾夕法尼亚大学医院完成了临床病理学住院医师培训。他正在扩大他的研究技能，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。他的顾问是医学博士 Jeffrey Weiser，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（人类铁代谢）、大卫·阿蒂斯博士组成。 （粘膜免疫）和迈克尔·梅（信号转导）。宾夕法尼亚大学的师资力量和设施使之成为完成该培训项目的理想环境。公共健康相关性：我们的粘膜提供了细菌感染的第一道屏障，这一关键功能对于免疫功能低下和危重患者尤其重要，该提案将研究抑制细菌生长的铁蛋白。通过了解铁运蛋白功能的机制，我们有可能开发出新的疗法来增强粘膜免疫或抑制阻碍粘膜免疫的细菌策略。

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.