Oxysterol Regulation of Microbial Pathogenesis

氧甾醇对微生物发病机制的调节

基本信息

批准号：
10381602
负责人：
Neal Mathew Alto
金额：
$ 57.36万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10381602
关键词：
25-hydroxycholesterol Acute Animal Model Animals Anti-Bacterial Agents B-Lymphocytes Bacteria Bacterial Infections Biochemical Biochemistry Biological Process Biophysics Biosensor Blood Circulation Cell membrane Cell physiology Cell surface Cells Chemicals Cholesterol Cholesterol Homeostasis Communicable Diseases Cultured Cells Development Distant Drug or chemical Tissue Distribution Endoplasmic Reticulum Epithelial Epithelial Cells Fatty Liver Functional disorder Genetic Glean Goals Gut Mucosa Heart Diseases Homeostasis Human Human Biology Immune Immune system Immunity Immunologics Infection Inflammasome Inflammatory Inflammatory Response Intracellular Membranes Lipids Listeria Listeria monocytogenes Listeriosis Mammalian Cell Mammals Mediating Membrane Membrane Proteins Membrane Structure and Function Metabolic Pathway Molecular Molecular Probes Monitor Movement Mucosal Immune System Mucous Membrane Mus Natural Immunity Organism Outcome Parasites Pathogenesis Pathogenicity Pathway interactions Pharmacology Physiological Play Process Production Property Protocols documentation Regulation Regulatory Pathway Resolution Role Shigella Shigella flexneri Signal Pathway Site Surface Surface Tension System Technology Testing Therapeutic Intervention Time Tissues Toxin Viral Virus Work adaptive immune response base biochemical tools cell growth cell motility cell type combat cytokine emerging pathogen gut bacteria gut colonization human pathogen in vivo innovation insight lipid metabolism live cell imaging macrophage microbial mouse model new technology novel therapeutics pathogen pathogenic bacteria pathogenic microbe prevent response small molecule transmission process

项目摘要

Project Summary The proposed project focuses on our recent discovery that immunological production of the oxysterol 25- Hydroxycholesterol (25HC) potently inhibits the cellular dissemination of two globally important bacterial pathogens, Listeria monocytogenes and Shigella flexneri. The anti-bacterial activity of 25HC is mediated through mobilization of the accessible cholesterol pool from the plasma membrane (PM). Accessible cholesterol is one of three pools into which PM cholesterol is sub-divided and this pool regulates cellular signaling pathways that control lipid homeostasis and cell growth. By first characterizing the molecular mechanism by which 25HC induces internalization of accessible cholesterol (Aim 1), these studies will reveal how cholesterol can be rapidly transported in response to cytokine stimulation. Second, we will determine how remodeling of PM cholesterol suppresses Listeria and Shigella from penetrating the cell-to-cell contact junctions of the mucosal epithelium (Aim 2). This work will reveal how mammals enhance the barrier function of mucosal surfaces through cholesterol metabolic pathways and will identify points of weakness in the mucosal immune system that may be exploited by numerous microbial pathogens. Third, we will develop new technologies for monitoring cholesterol dynamics in the living organism and use these technologies to determine the tissues and cell types that mobilize accessible cholesterol in response to bacterial infection (Aim 3). Finally, the physiological significance of oxysterol-mediated immune pathways will be investigated in mammalian model organisms using three complementary mouse models that disrupt 25HC activation, production, and downstream activity (Aim 4). Insights gleaned from these studies, which range from basic biochemistry to mouse models of infection, will explain how the human immune system has adapted fundamental aspects of cholesterol metabolism to protect barrier cells from intracellular bacterial infection. Developing new drugs that mimic the molecular activity of 25HC as determined in this proposal would be an innovative approach to combat human infectious disease associated with pathogens that exploit host cholesterol metabolism. These studies will also provide new insights into the pathogenic mechanisms of an important infectious disease-causing agent and also into the biology of the human inflammatory response.

项目概要拟议的项目重点关注我们最近的发现，即氧甾醇 25- 的免疫生产羟基胆固醇 (25HC) 有效抑制两种全球重要细菌的细胞传播病原体，单核细胞增生李斯特氏菌和福氏志贺氏菌。 25HC 的抗菌活性是介导的通过调动质膜 (PM) 中可利用的胆固醇库。无障碍胆固醇是 PM 胆固醇细分为的三个池之一，该池调节细胞控制脂质稳态和细胞生长的信号通路。首先通过表征分子 25HC 诱导可利用胆固醇内化的机制（目标 1），这些研究将揭示胆固醇如何响应细胞因子刺激而快速转运。其次，我们将确定如何 PM 胆固醇的重塑抑制李斯特菌和志贺氏菌穿透细胞间接触粘膜上皮连接处（目标 2）。这项工作将揭示哺乳动物如何增强屏障功能通过胆固醇代谢途径改变粘膜表面，并识别粘膜表面的弱点粘膜免疫系统可能被许多微生物病原体利用。三、我们将开发新的监测生物体内胆固醇动态的技术，并利用这些技术确定动员可利用的胆固醇以应对细菌感染的组织和细胞类型（目标 3）。最后，将研究氧甾醇介导的免疫途径的生理意义使用破坏 25HC 激活的三种互补小鼠模型的哺乳动物模型生物体，生产和下游活动（目标 4）。从这些研究中收集的见解包括基础知识生物化学到小鼠感染模型，将解释人类免疫系统如何适应胆固醇代谢的基本方面，以保护屏障细胞免受细胞内细菌感染。开发模仿本提案中确定的 25HC 分子活性的新药物将是一个对抗与利用宿主的病原体相关的人类传染病的创新方法胆固醇代谢。这些研究还将为疾病的致病机制提供新的见解。重要的传染病病原体，也涉及人类炎症反应的生物学。