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：
10274942
负责人：
Nan Yan
金额：
$ 48.13万
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/10274942
关键词：
Adaptor Signaling Protein Alzheimer&apos 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 brain tissue cell type cofactor frontotemporal lobar dementia-amyotrophic lateral sclerosis induced pluripotent stem cell inhibitor/antagonist 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.

C 型尼曼-匹克病 (NPC) 是一种致命的神经退行性疾病，由神经系统基因突变引起 NPC1 (95%) 和 NPC2 (5%) 基因的神经学特征与阿尔茨海默病惊人相似。疾病（AD），导致一些专家将 NPC 视为“儿童阿尔茨海默病”，FDA 没有批准治疗方法。然而，与鼻咽癌疾病相关的脂质和胆固醇缺陷是众所周知的。鼻咽癌疾病中神经炎症和浦肯野细胞死亡的免疫潜在途径仍然未知。我们最近发现先天免疫 STING 通路是由 NPC 缺陷和基因缺失激活的小鼠中的 STING 通路成分能够显着挽救 NPC 神经病理学的总体目标。该项目旨在了解 STING 如何驱动与 NPC 疾病相关的神经病理学。重点关注细胞内机制，我们将剖析 NPC 缺陷如何激活 STING 信号传导。目标2将重点关注脑组织病理学，全面测定STING表达细胞目标 3 将侧重于治疗评估、类型、活动及其对 NPC 疾病的功能贡献。我们将利用现有和新的 STING 途径治疗 Npc1-/- 小鼠和 NPC1 患者 iPSC 衍生细胞 STING 抑制剂与多种神经退行性疾病有关，包括帕金森病、这里提出的 ALS/FTD 和现在的 NPC1 将为人们提供急需的全面理解。 STING通路在大脑中的功能以及从STING激活到STING的逐步机制神经病理学。