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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.

尼曼-匹克病C型（NPC）是一种致命的神经退行性疾病，由神经细胞的基因突变引起