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Contribution of astrocytes to mutant FUS-linked Amyotrophic Lateral Sclerosis

星形胶质细胞对突变型 FUS 相关肌萎缩侧索硬化症的影响

基本信息

批准号：
10404651
负责人：
PIERA PASINELLI
金额：
$ 34.13万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-15 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10404651
关键词：
AMPA Receptors Adult Affect Amyotrophic Lateral Sclerosis Astrocytes Autocrine Communication Automobile Driving Autopsy Biological Assay Biology Brain Cause of Death Cell Death Cell Survival Cells Cessation of life Complex Conditioned Culture Media DNA Development Disease Disease Progression Environment Exposure to Feedback Functional disorder Genes Genotype Goals Human In Vitro Inflammatory Link Measures Mediating Messenger RNA Modeling Molecular Motor Motor Neurons Mus Mutation Neurodegenerative Disorders Neuroglia Neurons Nuclear Pathogenesis Pathogenicity Pathologic Pathology Pathway interactions Patients Pharmacology Phenotype Physiology Play Proteins Publishing RNA-Binding Proteins Reporter Rodent Role Signal Transduction Spatial Distribution Spinal Cord Standardization System TNF gene TNFRSF1A gene Testing Therapeutic Time Tissues Toxic effect base cell injury comparative cytokine excitotoxicity experimental study fused in sarcoma genetic manipulation human disease in vivo in vivo Model individualized medicine induced pluripotent stem cell motor behavior motor disorder motor impairment mouse model mutant mutant mouse model neuron loss neurotoxic overexpression prevent promoter single cell analysis sporadic amyotrophic lateral sclerosis vector

项目摘要

ABSTRACT The goal of this project is to identify the mechanisms by which mutations in Fused in Sarcoma (FUS) induce pathological and pathogenic changes in astrocytes in FUS-linked Amyotrophic Lateral Sclerosis (FUS-ALS). Astrocytes are known to contribute to disease progression in some, but not all, forms of ALS and, until recently, not much was known about the role of astrocytes in FUS-ALS. Our lab has recently published the first in vitro evidence that astrocytes expressing mutant forms of FUS (mutFUS), but not wild-type FUS, exert toxicity on motor neurons through activation of the NFkB pathway leading to the release of secreted factor(s), and primarily TNFα (Kia & McAvoy et al., GLIA, 2018). In a TNFα−dependent manner, motor neurons exposed to the conditioned medium of mutFUS astrocytes show AMPA receptor alterations that sensitize them to excitotoxic damage, leading to cell death. Activation of astrocytic NFkB and TNFα release seems to be specific to mutFUS-ALS, underscoring the importance of dissecting disease mechanisms specific to each form of ALS in order to develop tailored therapies. In this proposal, we will focus on mutFUS-ALS and will study (1) the mechanisms by which disease-casuative mutations in FUS alter astrocyte biology and (2) how mutant FUS expressing astrocyte affect the viability of other cells in the spinal cord in vivo. The ultimate goal is to identify key pathways targeted by mutFUS to eventually develop specific therapies. Ultimately, our models of FUS-ALS may serve as a platform for a comparative analysis with models mimicking other forms of ALS, so to identify genotype- specific vs. converging and more global mechanisms of disease pathogenesis. For our studies, we will use in vitro and in vivo models consisting of (1) primary rodent astrocytes transduced with different FUS mutations as well as iPSc-derived astrocytes from FUS patients; (2) an in vivo mouse model of mutFUS ALS. The in vitro systems will allow us to dissect the precise mechanisms by which mutFUS targets the astrocytes and to determine how mutFUS alters astrocyte biology in patients. The mouse model will allow us to study how mutFUS astrocytes affect the cellular environment in a complex in vivo setting.

摘要