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

基本信息

批准号：
10653132
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
项目类别：
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/10653132
关键词：
Adaptor Signaling Protein Alzheimer&apos s Disease Biology Brain Cell Death Cell Separation 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 Neimann-Pick&apos s Disease Type C Neurodegenerative Disorders Neurologic Niemann-Pick Diseases Parkinson Disease Pathology Pathway interactions Patients Process Proteins Proteomics Publishing Purkinje Cells Research Signal Transduction Splenomegaly Sting Injury Testing Therapeutic Tissues 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

项目摘要

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.

Niemann-Pick疾病C型（NPC）是由基因突变引起的致命神经退行性疾病 NPC1（95％）和NPC2（5％）基因。 NPC熊的神经功能与阿尔茨海默氏症的相似之处疾病（AD），导致一些专家将NPC视为“童年时期的阿尔茨海默氏症”。没有FDA批准的疗法可用。与NPC疾病相关的脂质和胆固醇缺陷已得到充分了解。然而， NPC疾病中神经炎症和浦肯野细胞死亡的背后的免疫途径尚不清楚。我们最近发现，先天免疫刺激途径被NPC缺陷和遗传缺失激活小鼠中的刺激途径成分能够显着挽救NPC神经病理学。总体目标该项目旨在了解Sting如何驱动与NPC疾病相关的神经病理学。目标1意志专注于细胞内机制，我们将剖析NPC缺陷如何激活刺激信号。 AIM 2将集中于脑组织病理学，我们将全面确定刺痛表达细胞类型，活动及其对NPC疾病的功能贡献。 AIM 3将专注于热评估，我们将在其中处理NPC1 - / - 小鼠和NPC1患者IPSC衍生的细胞，并具有现有和新的Sting途径抑制剂。在包括帕金森氏病的几种神经退行性疾病中隐含了Sting ALS/FTD和现在的NPC1。这里提出的研究将为人们提供急需的全面了解大脑中的刺激途径功能以及从st刺激活到的逐步机制神经病理学。