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:9220407
- 负责人:
- 金额:$ 52.47万
- 依托单位:
- 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 2021-08-31
- 项目状态:已结题
- 来源:
- 关键词:AffectAmyotrophic Lateral SclerosisAnimal ModelAxonAxonal TransportBehaviorBehavioralBindingBinding ProteinsBiochemical ProcessBiological ModelsBiologyBrainBuffersCRISPR/Cas technologyCalciumCell physiologyCellsCellular biologyDataDefectDegenerative DisorderDiseaseElectron MicroscopyEngineeringEtiologyFamilial Amyotrophic Lateral SclerosisFamilyGenesGeneticGenetic EngineeringGoalsHousingHumanImpairmentInheritedInvestigationKnock-inLaboratoriesLaboratory PersonnelLinkMembrane PotentialsMitochondriaMitochondrial SwellingModelingMolecular TargetMorphologyMotorMotor NeuronsMusMutationNatureNeurodegenerative DisordersNeuronsNuclearOutcomeOxidation-ReductionOxidative PhosphorylationPathogenicityPathologicPathologyPatientsPhenotypePhysiologicalPositioning AttributePreventionProcessProteinsReagentResearchResourcesRodent ModelRoleSpinal CordSubgroupSurveysSwellingSystemTechniquesTestingTissuesTransgenic MiceWorkbasecell typedisease mechanisms studydisease-causing mutationgain of functionhuman diseasein vivoinduced pluripotent stem cellinsightknock-downmitochondrial dysfunctionmotor deficitmouse modelmutantnervous system disordernoveloverexpressionresearch studyresponseskillstrait
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
项目成果
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{{ truncateString('TEEPU SIDDIQUE', 18)}}的其他基金
A novel innate immunity risk factor for amyotrophic lateral sclerosis
肌萎缩侧索硬化症的新先天免疫危险因素
- 批准号:
10220811 - 财政年份:2019
- 资助金额:
$ 52.47万 - 项目类别:
A novel innate immunity risk factor for amyotrophic lateral sclerosis
肌萎缩侧索硬化症的新先天免疫危险因素
- 批准号:
10006773 - 财政年份:2019
- 资助金额:
$ 52.47万 - 项目类别:
Investigation of ALS caused by mutant CHCHD10
CHCHD10 突变体引起的 ALS 的研究
- 批准号:
9751413 - 财政年份:2016
- 资助金额:
$ 52.47万 - 项目类别:
Investigation of ALS caused by mutant CHCHD10
CHCHD10 突变体引起的 ALS 的研究
- 批准号:
9983200 - 财政年份:2016
- 资助金额:
$ 52.47万 - 项目类别:
Association of ALS to gene-environment mediated changes in HDL proteins
ALS 与基因环境介导的 HDL 蛋白变化的关联
- 批准号:
8760313 - 财政年份:2013
- 资助金额:
$ 52.47万 - 项目类别:
Association of ALS to gene-environment mediated changes in HDL proteins
ALS 与基因环境介导的 HDL 蛋白变化的关联
- 批准号:
8609030 - 财政年份:2013
- 资助金额:
$ 52.47万 - 项目类别:
Association of ALS to gene-environment mediated changes in HDL proteins
ALS 与基因环境介导的 HDL 蛋白变化的关联
- 批准号:
8422569 - 财政年份:2013
- 资助金额:
$ 52.47万 - 项目类别:
Association of ALS to gene-environment mediated changes in HDL proteins
ALS 与基因环境介导的 HDL 蛋白变化的关联
- 批准号:
8960824 - 财政年份:2013
- 资助金额:
$ 52.47万 - 项目类别:
Role of High Density Lipoprotein Particles in amyotrophic lateral sclerosis
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- 批准号:
8469190 - 财政年份:2012
- 资助金额:
$ 52.47万 - 项目类别:
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