Mechanism of STING-mediated Neuropathology in Niemann-Pick Disease

STING 介导的尼曼-皮克病神经病理学机制

• 批准号: 10454283
• 负责人: Nan Yan
• 金额: $ 48.15万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10454283
• 关键词: Adaptor Signaling Protein; Alzheimer' s Disease; Biology; Brain; Cell Death; Cell Survival; Cells; Cerebellum; Cessation of life; Childhood; Cholesterol; Clinical; Cre-LoxP; Cyclic GMP; Cyclodextrins; DNA; DNA Sequence Alteration; Data; Defect; Disease; Endoplasmic Reticulum; FDA approved; Future; Genes; Genetic; Goals; Golgi Apparatus; Hepatomegaly; IRF3 gene; Immune; Integral Membrane Protein; Interferons; Knock-out; Knockout Mice; Label; Ligands; Lipids; Lysosomes; Mediating; Microglia; Modeling; Mus; NPC1 gene; Natural Immunity; Neurodegenerative Disorders; Neurologic; Niemann-Pick Diseases; Parkinson Disease; Pathology; Pathway interactions; Patients; Process; Proteins; Proteomics; Publishing; Purkinje Cells; Research; Signal Transduction; Splenomegaly; Sting Injury; Supraoptic Vertical Ophthalmoplegia; Testing; Therapeutic; Tissues; Ursidae Family; Wild Type Mouse; antagonist; brain tissue; cell type; cofactor; frontotemporal lobar dementia-amyotrophic lateral sclerosis; induced pluripotent stem cell; inhibitor; innate immune pathways; innovation; microbial; motor function improvement; nervous system disorder; neuroinflammation; neuron loss; neuropathology; prevent; progressive neurodegeneration; sensor; single-cell RNA sequencing; targeted treatment; trafficking; transcription factor

Niemann-Pick disease type C (NPC) is a fatal neurodegenerative disease caused by genetic mutations in the NPC1 (95%) and NPC2 (5%) genes. Neurological features of NPC bear striking resemblances with Alzheimer’s disease (AD), leading to some experts considering NPC as “Childhood Alzheimer’s”. No FDA-approved therapy is available. Lipids and cholesterol defects associated with the NPC disease are well understood. However, immune pathways underlying neuroinflammation and Purkinje cell death in the NPC disease remain unknown. We recently found that the innate immune STING pathway is activated by NPC-deficiency, and genetic deletions of STING pathway components in mice are able to remarkably rescue NPC neuropathology. The overall goal of this project is to understand how STING drives neuropathology associated with the NPC disease. Aim 1 will focus on intracellular mechanisms, where we will dissect how STING signaling is activated by NPC-deficiency. Aim 2 will focus on brain tissue pathology, where we will comprehensively determine STING expression cell types, activities and their functional contribution to the NPC disease. Aim 3 will focus on therapeutic assessment, where we will treat Npc1-/- mice and NPC1 patient iPSC-derived cells with existing and new STING pathway inhibitors. STING has been implicated in several neurodegenerative diseases including Parkinson’s disease, ALS/FTD and now NPC1. Studies proposed here will provide a much-needed comprehensive understanding of STING pathway function in the brain as well as a step-by-step mechanism from STING activation to neuropathology.

C型尼曼-匹克病（NPC）是一种致命的神经退行性疾病， NPC 1（95%）和NPC 2（5%）基因。鼻咽癌的神经系统特征与阿尔茨海默病有显著的相似性 由于NPC是阿尔茨海默病（AD）的一种，导致一些专家将NPC视为“儿童阿尔茨海默病”。没有FDA批准的治疗 服务器租用-美国服务租用与NPC疾病相关的脂质和胆固醇缺陷是众所周知的。然而，在这方面， NPC疾病中神经炎症和浦肯野细胞死亡的免疫途径仍然未知。 我们最近发现，先天免疫STING途径被NPC缺陷和基因缺失激活， STING通路组分的小鼠中的表达能够显著地挽救NPC神经病理学。的总目标 本项目旨在了解STING如何驱动与NPC疾病相关的神经病理学。目标1将 重点是细胞内的机制，在那里我们将剖析如何STING信号被激活的NPC缺陷。 目的2将重点放在脑组织病理学上，在那里我们将全面地确定STING表达细胞， 类型，活动及其对NPC疾病的功能贡献。目标3将侧重于治疗评估， 我们将用现有的和新的STING途径处理Npc 1-/-小鼠和NPC 1患者iPSC衍生的细胞， 抑制剂的STING与几种神经退行性疾病有关，包括帕金森病， ALS/FTD和现在的NPC 1。这里提出的研究将提供一个急需的全面了解， STING通路在大脑中的功能以及从STING激活到 神经病理学