The Mitochondrion-STING Axis in An Early Childhood Onset Neurodegenerative Disease

儿童早期发病的神经退行性疾病中的线粒体-STING 轴

基本信息

批准号：
10297664
负责人：
Nan Yan
金额：
$ 46.66万
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：
2021-09-15 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10297664
关键词：
Affect Amyotrophic Lateral Sclerosis Bacteria Behavior Biochemical Biology Brain Cells Cerebellum Chronic Complex Congenital Disorders Cre driver Cytosol DNA Data Defect Dependence Development Developmental Delay Disorders Disease Embryo Exhibits Extravasation Genes Genetic Goals Human Immune Immune signaling Immunology In Situ Inflammation Interferons Internal Ribosome Entry Site Knock-out Knockout Mice Mediating Mendelian disorder Microcephaly Mitochondria Mitochondrial DNA Modeling Molecular Molecular Genetics Motor Mus Mutation Nerve Degeneration Neurodegenerative Disorders Neuroglia Neurologic Neurons Online Mendelian Inheritance In Man Parkinson Disease Pathologic Pathology Pathway interactions Patients Pharmaceutical Preparations Purkinje Cells Rattus Reporter Role Seizures Signal Pathway Signal Transduction Specificity Stimulator of Interferon Genes Sting Injury Stress Technology Therapeutic Time brain cell cell type early childhood early onset induced pluripotent stem cell inhibitor/antagonist mRNA Expression mortality mouse model nervous system disorder neuron loss neuropathology response single cell analysis single-cell RNA sequencing targeted treatment

项目摘要

PROJECT SUMMARY Mitochondria are powerhouses of the cell that are often viewed as bacteria living in the cytosol. Stressed or damaged mitochondria induce inflammation through activation of multiple innate immune signaling pathways including the DNA sensing cGAS-STING pathway. We recently showed that deficiency of a cytoplasmic deglycosylase NGLY1 results in mitochondrial damage and potent activation of the STING pathway. Mutations in the NGLY1 gene are associated with an early childhood onset neurodegenetive disease with high mortality and no therapy. We recently established and characterized a Ngly1-deficient mouse model that develop early onset and progressive deteriorating coordination and motor functions. We also present exciting molecular and genetic evidence that implicate the mitochondrion-STING axis in neuropathology. The overall goal of this project is to define the neuro-pathological mechanism of NGLY1-deficiency, with a strong focus on the mechanism of the mitochondrion-STING axis. Aim 1 will define cell type specificity through genetic and single-cell approaches. Aim 2 will dissect intracellular signaling pathways in neuronal and glial cells. Aim 3 will evaluate therapies targeting the mitochondrion-STING axis. Studies proposed here should reveal the central mechanism of the mitochondrion-STING axis in neuropathology and neurodegeneration, which will have broad implications in many complex neurogenerative diseases that are affecting millions of people.

项目摘要线粒体是细胞的动力室，通常被视为生活在细胞质中的细菌。强调或通过激活多个先天免疫信号通路来诱导线粒体诱导炎症包括DNA感应CGAS-sting途径。我们最近表明细胞质缺乏脱糖基酶NGLY1导致线粒体损伤和刺激途径的有效激活。突变在NGLY1中，基因与幼儿发作神经退行性疾病有关没有治疗。我们最近建立并表征了NGLY1缺陷的小鼠模型，该模型早期发展发作和进行性降低的协调和运动功能。我们还提出令人兴奋的分子和在神经病理学中暗示线粒体刺激轴的遗传证据。该项目的总体目标是定义NGLY1缺乏性的神经病理学机制，重点是线粒体圣轴。 AIM 1将通过遗传和单细胞方法来定义细胞类型的特异性。 AIM 2将剖析神经元和神经胶质细胞中的细胞内信号通路。 AIM 3将评估疗法靶向线粒体刺。这里提出的研究应揭示神经病理学和神经变性中的线粒体刺激轴，这将在许多人中具有广泛的影响影响数百万人的复杂神经发生疾病。