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：
10592354
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/10592354
关键词：
25-hydroxycholesterol Acute Animals Anti-Bacterial Agents B-Lymphocytes Bacteria Bacterial Infections Biochemical Biochemistry Biological Process Biophysics Biosensor Cell membrane Cell physiology Cell surface Cells Chemicals Cholesterol Cholesterol Homeostasis Circulation Communicable Diseases Cultured Cells Development Distant Drug or chemical Tissue Distribution Endoplasmic Reticulum Epithelial Cells Epithelium 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 Innate Immune Response Intracellular Membranes Lipids Listeria Listeria monocytogenes Listeriosis Macrophage 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 Penetration 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 Visualization Work adaptive immune response 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 microbial model organism mouse model new technology novel therapeutics pathogen pathogenic bacteria pathogenic microbe pharmacologic 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.

项目摘要拟议的项目的重点是我们最近发现的氧化酚的免疫学生产25- 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，李斯特菌单核细胞增生和志贺氏菌屈曲。介导25HC的抗细菌活性通过动员质膜（PM）的可访问胆固醇池。可访问胆固醇是PM胆固醇被细分的三个水池之一，该池调节细胞控制脂质稳态和细胞生长的信号通路。首先表征分子 25HC诱导可及胆固醇内在化的机制（AIM 1），这些研究将揭示如何响应细胞因子刺激而迅速转运胆固醇。第二，我们将确定如何 PM胆固醇的重塑可抑制李斯特菌和志贺氏菌，从而穿透细胞对细胞接触粘膜上皮的连接处（AIM 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的粘膜表面的粘膜表面，将确定弱点粘膜免疫系统可能被许多微生物病原体所利用。第三，我们将开发新的监测活有机体中胆固醇动态的技术，并使用这些技术来确定针对细菌感染动员可及胆固醇的组织和细胞类型（AIM 3）。最后，将研究氧化酚介导的免疫途径的生理意义使用三种破坏25HC激活的互补小鼠模型的哺乳动物模型生物，生产和下游活动（目标4）。这些研究收集的见解，范围从基本对小鼠感染模型的生物化学将解释人类免疫系统如何适应胆固醇代谢的基本方面可保护屏障细胞免受细胞内细菌感染的影响。开发出模仿25HC分子活性的新药物，如本提案中所确定的那样抗击与病原体相关的人类传染病的创新方法胆固醇代谢。这些研究还将提供有关一种致病机制的新见解重要的引起感染性疾病的药物，也进入人类炎症反应的生物学。