Integration of host lipid metabolism and innate immunity in microbial infection

项目摘要：本提案的目标是深入了解东道主 脂蛋白和磷脂代谢影响对分枝杆菌感染的免疫应答。 初步数据显示，感染的巨噬细胞在麻风皮损和体外积聚宿主- 衍生的氧化磷脂，抑制先天免疫。值得注意的是，正常的高密度脂蛋白 氧化磷脂的清除剂和反向脂质转运的介体高密度脂蛋白(HDLE)可以保存天然的 分枝杆菌感染时的免疫反应。这一建议旨在：1)检验不同于 巨噬细胞亚群在进展型麻风中介导氧化脂蛋白的摄取，2)决定 脂肪堆积对先天免疫反应和分枝杆菌生长的影响，以及3)决定 诱导脂质反向转运的药物可以保护先天免疫反应并限制分枝杆菌 成长。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：主要研究人员为助理教授，拥有博士学位 心脏病学和免疫学方面的培训。他所受训练的广度为他的怀孕和 这一建议的综合，横跨先天性免疫、传染病和脂蛋白等领域 新陈代谢：候选人将在世界知名免疫学家罗伯特·莫德林的指导下 在加州大学洛杉矶分校。 目标和职业发展：近期目标将是探索宿主脂质的整合 以麻风为模型研究微生物感染中的代谢与先天免疫。长期目标将是 利用这一经验成为一名成熟的研究人员，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。 报告摘要：分枝杆菌引起发病率和死亡率的部分原因是逃避宿主免疫。这 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同源来恢复宿主免疫反应的新策略。 相关性(请参阅说明)： 对麻风的研究帮助建立了免疫学范式，包括1型和2型免疫和 Toll样受体在微生物感染中的作用通过这份提案中的工作，我们将定义关键 在慢性炎症中具有不同表型和功能的巨噬细胞亚群--发现 我们相信，这将直接适用于其他更常见的疾病，如动脉粥样硬化。

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.