Integration of host lipid metabolism and innate immunity in microbial infection

描述（由申请方提供）：项目总结：本提案的目的是深入了解宿主脂蛋白和磷脂代谢影响分枝杆菌感染免疫应答的机制。初步数据表明，麻风病病灶和体外感染的巨噬细胞积累宿主来源的氧化磷脂，抑制先天免疫。值得注意的是，正常的高密度脂蛋白（HDL），氧化磷脂的清除剂和脂质反向转运的介质可以在分枝杆菌感染期间保持先天免疫应答。该提案旨在：1）检验不同的巨噬细胞亚群介导麻风进行性形式中氧化脂蛋白的摄取的假设，2）确定脂质积累对先天免疫应答和分枝杆菌生长的影响，和3）确定诱导反向脂质转运的试剂是否可以保持先天免疫应答并限制分枝杆菌生长。重要的是，这项工作代表了一种针对分枝杆菌病原体的新治疗策略。候选人和环境：主要研究者是一名助理教授，接受过心脏病学和免疫学博士培训。他的培训广度允许这个提案的概念和合成，它跨越先天免疫，传染病和脂蛋白代谢领域：候选人将在加州大学洛杉矶分校世界知名的免疫学家Robert Modlin的指导下。目标和职业发展：近期的目标将是探索宿主脂质代谢和先天免疫在微生物感染中的整合，以麻风病为模型。长期的目标是利用这些经验成为一个成熟的研究者，可以将这些免疫学原理应用于“慢性炎症性疾病，如动脉粥样硬化”。摘要：分枝杆菌通过逃避宿主免疫而引起发病和死亡。该提案探讨了宿主脂质的氧化如何在抑制宿主免疫防御中发挥重要作用，并将探索通过恢复脂质homeosatis来恢复宿主免疫反应的新策略。相关性（参见说明）：麻风病的研究有助于建立免疫学范式，包括1型和2型免疫以及Toll样受体在微生物感染中的功能。通过这项提案中的工作，我们将定义在慢性炎症中具有不同表型和功能的关键巨噬细胞亚群-我们认为这些发现将直接适用于其他更普遍的疾病，如动脉粥样硬化。 (End摘要）

DESCRIPTION (provided by applicant): PROJECT SUMMARY: The objective of this proposal is to gain insight into the mechanisms by which host lipoprotein and phospholipid metabolism influence the immunologic response to mycobacterial infection. Preliminary data demonstrate that infected macrophages in leprosy lesions and in vitro accumulate host- derived oxidized phospholipids that inhibit innate immunity. Remarkably, normal high density lipoprotein (HDL), a scavenger of oxidized phospholipids and mediator of reverse lipid transport can preserve innate immune responses during mycobacterial infection. This proposal aims to: 1) test the hypothesis that distinct macrophage subsets mediate uptake of oxidized lipoproteins in the progressive form of leprosy, 2) determine the effects of lipid accumulation on innate immune responses and mycobacterial growth, and 3) determine if agents that induce reverse lipid transport can preserve innate immune responses and restrict mycobacterial growth. Importantly, this work represents a novel therapeutic strategy against mycobacterial pathogens. CANDIDATE AND ENVIRONMENT: The principal investigator is an Assistant Professor with doctoral training in both cardiology and immunology. The breadth of his training allowed for the conception and synthesis of this proposal, which spans the fields of innate immunity, infectious disease, and lipoprotein metabolism: The candidate will be under the mentorship of Robert Modlin, a world-renowned immunologlst at UCLA. GOALS AND CAREER DEVELOPMENT: The immediate goal will be to explore the integration of host lipid metabolism and innate immunity in microbial infection, using leprosy as a model. The long term goal will be to use this experience to become an established investigator that can apply these immunogic principles to " chronic inflammatory diseases, such as atherosclerosis. LAY SUMMARY: Mycobacteria cause morbidity and mortality in part by evading host immunity. This proposal explores how oxidation of host lipids plays an important role in inhibiting host immune defenses, and will explore novel strategies to regain host immune responses by restoring lipid homeosatis. RELEVANCE (See instructions): Studies in leprosy have helped establish immunologic paradigms, including type 1 and type 2 immunity and the funciton of Toll like receptors in microbial infection. Through the work in this proposal, we will define key macrophage subsets that possess divergent phenotype and function in chronic inflammation- findings that we believe that will be directly applicable to other more prevalent diseases, such as atherosclerosis. (End of Abstract)