The Role of Schwann Cell Lipid Droplets In Neuropathology of Leprosy

雪旺细胞脂滴在麻风病神经病理学中的作用

基本信息

批准号：
10674122
负责人：
John T Belisle
金额：
$ 17.79万
依托单位：
COLORADO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-17 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10674122
关键词：
Address Affect Annual Reports Axon Bacillus Bacteria Bacterial Infections Binding Biochemical Biological Brazil Case Study Catabolism Cells Cellular Metabolic Process Cholesterol Cholesterol Homeostasis Chronic Granulomatous Disease Country Cytochromes Deformity Demyelinations Detection Diagnosis Discrimination Disease Dystroglycan Enzymes Epidemiology Equilibrium Etiology Event Fiber Fibrosis Functional disorder Generations Growth Homeostasis Human Impairment India Infection Innate Immune Response Intervention Laminin Lead Leprosy Ligands Lipid IV Lipids Metabolism Molecular Mycobacterium leprae Myelin Myelin Sheath NADH NADP Nerve Neurons Neuropathogenesis Neuropathy Oxidoreductase PPAR gamma Pathogenesis Pathogenicity Patients Peripheral Peripheral Nerves Pharmacotherapy Play Population Prevalence Production Proliferating Proteins Public Health Receptor Cell Reporting Research Role Schwann Cells Signal Transduction Surface Symptoms TLR6 gene Temperature Sense Testing Touch sensation Tropism base cell envelope global health in vivo inhibitor lipid metabolism lipidomics mannose receptor myelination nerve damage neuropathology novel overtreatment oxidation pathogen physically handicapped prevent receptor relating to nervous system therapy development transcription factor transmission process

项目摘要

Summary Leprosy is no longer designated as a global health problem by the WHO (defined by a registered prevalence of less than one case of leprosy per 10,000 population); however, about 200,000 new cases are still reported each year. Recently several epidemiological reports based on “find-and-treat” campaigns have indicated under reporting and suggested “hidden-leprosy”. This, as well as the identification of environmental reservoirs, would explain the continued transmission of the etiological agent, Mycobacterium leprae, in the human population. The most pronounced forms of this disease manifest with sever deformities and physical disabilities that are a result of irreversible nerve damage caused by the pathogen's tropism for peripheral nerves. Specifically, M. leprae has evolved and adapted to infect and survive in Schwann cells (SCs), where defined host-pathogen interactions result in demyelination and nerve fibrosis. The molecular and biochemical interactions of M. leprae and SCs have not been well defined. Thus, elucidating these interactions and their downstream consequences is essential to understand the neuropathogenesis of leprosy and to develop appropriate interventions. The ability of M. leprae to induce lipid droplet formation in SCs has been established as key and fundamental aspect of M. leprae pathogenicity. As such, the focus of the proposed research is to define the molecular interactions that result in lipid droplet formation by M. leprae infected SCs and understand how M. leprae utilizes lipids from these droplets to support its growth and drive pathogenesis. These objectives are based on the unifying hypothesis that, via surface ligands M. leprae gains access to SCs and induces lipid droplet formation. The pathogen modulation of host cell lipid metabolism promotes SC dysfunction and the generation of a permissive innate immune response that facilitates bacilli persistence in the nerve. Further, M. leprae catabolism of the lipid droplet associated cholesterol supports the pathogens intracellular growth, as well as drives cell signaling events that result in impairment of myelin production and stability.

概括世界卫生组织不再将麻风病指定为全球健康问题（定义为已登记的麻风病患病率）每 10,000 人中麻风病病例不到 1 例）；然而，每年仍报告约 200,000 例新病例最近，一些基于“发现和治疗”活动的流行病学报告表明。报告并建议“隐性麻风病”，以及识别环境储存库。解释了病原体麻风分枝杆菌在人群中的持续传播。这种疾病最明显的形式表现为严重的畸形和身体残疾，从而导致病原体对周围神经的趋向性导致不可逆的神经损伤。进化并适应在施万细胞（SC）中感染和生存，其中确定了宿主与病原体的相互作用导致脱髓鞘和神经纤维化。麻风分枝杆菌和 SC 的分子和生化相互作用。因此，阐明这些相互作用及其下游后果至关重要。了解麻风病的神经发病机制并制定适当的干预措施。诱导 SC 中脂滴形成已被确定为麻风分枝杆菌的关键和基本方面因此，拟议研究的重点是定义导致致病性的分子相互作用。麻风分枝杆菌感染的 SC 形成脂滴，并了解麻风分枝杆菌如何利用这些液滴中的脂质支持其生长并驱动发病机制，这些目标基于以下统一假设：表面配体麻风分枝杆菌获得 SC 并诱导脂滴形成。宿主细胞脂质代谢促进 SC 功能障碍和允许的先天免疫反应的产生这有利于杆菌在神经中的持久存在，此外，麻风分枝杆菌对脂滴的分解代谢也与之相关。胆固醇支持病原体的细胞内生长，并驱动细胞信号事件，从而导致髓磷脂的产生和稳定性受损。