权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Investigation of ALS caused by mutant CHCHD10

CHCHD10 突变体引起的 ALS 的研究

基本信息

批准号：
9983200
负责人：
TEEPU SIDDIQUE
金额：
$ 50.73万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9983200
关键词：
ALS patients Affect Amyotrophic Lateral Sclerosis Animal Model Axon Axonal Transport Behavior Behavioral Binding Binding Proteins Biochemical Process Biological Models Biology Brain Buffers CRISPR/Cas technology Calcium Cell physiology Cells Cellular biology Data Defect Degenerative Disorder Disease Electron Microscopy Engineering Etiology Familial Amyotrophic Lateral Sclerosis Family Genes Genetic Genetic Engineering Goals Human Impairment Inherited Investigation Knock-in Laboratories Laboratory Personnel Link Membrane Potentials Mitochondria Mitochondrial Swelling Modeling Molecular Target Morphology Motor Neurons Mus Mutation Nature Neurodegenerative Disorders Neurons Nuclear Outcome Oxidation-Reduction Oxidative Phosphorylation Pathogenicity Pathologic Pathology Patients Periodicity Phenotype Physiological Positioning Attribute Prevention Process Proteins Reagent Research Resources Rodent Model Role Spinal Cord Subgroup Surveys Swelling System Techniques Testing Tissues Transgenic Mice base cell type disease mechanisms study disease-causing mutation experimental study gain of function human disease in vivo induced pluripotent stem cell insight knock-down mitochondrial dysfunction motor deficit motor impairment mouse model mutant nervous system disorder novel overexpression response skills trait

项目摘要

Some of the most robust advances in the understanding of amyotrophic lateral sclerosis (ALS), a multi- etiologic and fatal disorder of the nervous system, have come from the identification of the genetic basis of a subgroup of ALS cases. In this subgroup of ALS (familial ALS or FALS), the disease is inherited as a familial trait. Identification of a single mechanism of disease across all of ALS has been elusive, but notable amongst proposed common mechanisms is mitochondrial dysfunction. However, till recently, no direct robust etiological link between mitochondrial genes, nuclear or mitochondrial, had been found. Recently, others and we found that mutations in a gene called CHCHD10 causes ALS and additional phenotypes. Some other ALS genes, including VCP, HNRNPA1, SQSTM1 and OPTN are also associated with other phenotypes besides ALS. CHCHD10 and its protein product are not well studied. To investigate how a mutation in CHCHD10 may cause ALS, we have collected or developed promising reagents and assembled collaborators and laboratory personnel with specialized skills in genetic engineering, rodent models, cell biology, CRISPR/Cas9 gene editing, mitochondrial function, redox response, induced pluripotent stem cell (iPSC) derived motor neurons and primary motor neurons to carry out the proposed experiments in my laboratory and the laboratories of collaborators. We will investigate the pathology and behavior of a new transgenic mouse model we have engineered to overexpress the mutant (R15L) human CHCHD10 gene. Preliminary study shows axonal pathology in the spinal cord and brain of this mouse with periodic beaded axonal swellings harboring mitochondria. Additional more precise models will also be developed. To determine what aspect of mitochondrial function or morphology is affected by mutant CHCHD10 we will screen mitochondrial function of energetics, redox studies, calcium buffering and electron microscopy analysis. We will identify the binding protein partner(s) of CHCHD10 protein to understand the role of CHCHD10 in the mitochondrial biology. On completion, our study would provide a clearer understanding of the central defect(s) in this form of ALS and potentially a more granular understanding of mitochondrial defect generalizable across ALS. The study will also allow the identification of potential molecular targets for rational therapy and/or prevention of ALS.

对肌萎缩性侧索硬化症（ALS）的了解取得了一些最有力的进展