The host mucosal response to microbial iron metabolism

描述（由申请人提供）：此提案描述了一个为期5年的临床病理学和微生物学学术生涯的培训计划。本研究将探讨细菌铁代谢的粘膜炎症反应。为了应对不同的细菌，呼吸道黏膜分泌脂钙素（脂钙素2），这是一种结合细菌铁清除分子肠杆菌蛋白的小蛋白质。铁铁苷从细菌中分离铁，并能阻止肠杆菌依赖细菌的复制。在细胞培养中，与肠杆菌蛋白结合的1铁苷酸引起趋化因子IL-8的释放，表明它具有额外的促炎作用。本研究计划将基于其结合肠obactin的铁状态，通过以下目的来验证siderocalin介导粘膜炎症反应的假设：1)确定siderocalin在体内是否介导对细菌的粘膜炎症反应。该项目将使用鼻腔定植和肺炎、铁霉素敲除小鼠和等基因肺炎克雷伯氏菌肠杆菌突变体的动物模型来测量铁霉素对细菌生长、趋化因子产生和中性粒细胞募集的影响。2)鉴定体外响应铁苷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铁钙素受体和趋化因子调节蛋白的需求，以响应铁铁钙素。首席研究员Michael Bachman医学博士，在宾夕法尼亚大学医院完成了他的临床病理学实习。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。他的导师是Jeffrey Weiser医学博士，一位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，他建立了一个由Robert Wilson医学博士（人体铁代谢），David Artis博士（粘膜免疫）和Michael May（信号转导）组成的科学咨询委员会。宾夕法尼亚大学的师资和设施使其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，这是一项至关重要的功能，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苷蛋白。通过了解siderocalin的功能机制，我们可以开发新的治疗方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.