Integration of host lipid metabolism and innate immunity in microbial infection

微生物感染中宿主脂质代谢和先天免疫的整合

• 批准号: 7912986
• 负责人: DANIEL CRUZ
• 金额: $ 10.57万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-08 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7912986
• 关键词: Affect; Antigen Presentation Pathway; Atherosclerosis; CD209 gene; Cardiology; Characteristics; Chronic; Clinical; Communicable Diseases; Conceptions; Data; Diabetes Mellitus; Disease; Doctor of Medicine; Doctor of Philosophy; Environment; Foam Cells; Genus Mycobacterium; Goals; Growth; High Density Lipoproteins; Human; Immune; Immune response; Immunity; Immunologics; Immunology; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Response; Instruction; L Forms; Leprosy; Lesion; Lipids; Lipoprotein (a); Lipoproteins; Mediating; Mediator of activation protein; Mentorship; Metabolism; Modeling; Morbidity - disease rate; Mycobacterium Infections; Natural Immunity; Pathogenesis; Pattern; Phagocytosis; Phenotype; Phospholipid Metabolism; Phospholipids; Play; Principal Investigator; Publishing; Regulation; Research Personnel; Role; Testing; Therapeutic Intervention; Toll-like receptors; Training; Vitamin D; Work; abstracting; antimicrobial; career development; cytokine; experience; innate immune function; insight; lipid metabolism; lipid transport; macrophage; microbial; monocyte; mortality; mycobacterial; novel strategies; novel therapeutics; oxidation; oxidized low density lipoprotein; pathogen; professor; response; scavenger receptor; uptake

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)

描述(由申请人提供)：项目摘要：这项建议的目的是深入了解宿主脂蛋白和磷脂代谢影响对分枝杆菌感染的免疫反应的机制。初步数据表明，在麻风皮损和体外感染的巨噬细胞积累宿主衍生的氧化磷脂，抑制天然免疫。值得注意的是，正常的高密度脂蛋白(HDL)是氧化磷脂的清除剂和反向脂质运输的媒介，在分枝杆菌感染期间可以保护先天免疫反应。这一建议的目的是：1)检验不同的巨噬细胞亚群在进行性麻风中介导氧化脂蛋白摄取的假说；2)确定脂质积聚对先天性免疫反应和分枝杆菌生长的影响；3)确定诱导脂质反向转运的药物是否可以保护先天性免疫反应并限制分枝杆菌的生长。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：首席研究员是一名助理教授，曾在心脏病学和免疫学方面接受博士培训。他的培训范围广泛，使这项横跨先天性免疫、传染病和脂蛋白新陈代谢领域的提案得以构思和合成：候选人将在加州大学洛杉矶分校世界知名免疫学家罗伯特·莫德林的指导下。目标和职业发展：近期目标将是以麻风病为模型，探索宿主脂代谢和天然免疫在微生物感染中的整合。长期目标将是利用这一经验成为一名成熟的研究人员，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。这项建议探讨了宿主脂质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(见说明)：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-我们相信这一发现将直接适用于其他更常见的疾病，如动脉粥样硬化。(摘要结束)