VCP in myopathy and dementia

VCP 在肌病和痴呆中的作用

• 批准号: 10356903
• 负责人: CONRAD C WEIHL
• 金额: $ 73.67万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10356903
• 关键词: Affect; Age of Onset; Amyotrophic Lateral Sclerosis; Autophagocytosis; Autophagosome; Binding; Biogenesis; Brain; Cell physiology; Cells; Complex; Data; Degenerative Disorder; Dementia; Disease; Endocytosis; Frontotemporal Dementia; Functional disorder; Genetic Diseases; Goals; Homeostasis; Impairment; Inclusion Bodies; Inclusion Body Myopathy with Early-Onset Paget Disease; Inherited; Lysosomes; Maintenance; Mediating; Mediator of activation protein; Membrane; Missense Mutation; Molecular; Mus; Muscle; Muscle Cells; Muscle Fibers; Muscle Weakness; Mutant Strains Mice; Mutation; Myopathy; Nerve Degeneration; Nervous system structure; Neurons; Nutrient; Osteitis Deformans; Parkinson Disease; Pathogenesis; Pathogenicity; Pathologic; Pathology; Pathway interactions; Patients; Process; Proteins; Research; Role; Rupture; Seeds; Signal Pathway; Signal Transduction; Skeletal Muscle; System; TDP-43 aggregation; Ubiquitin; Vacuole; Work; age group; alpha synuclein; cofactor; detection of nutrient; frontotemporal lobar dementia-amyotrophic lateral sclerosis; human tissue; induced pluripotent stem cell; motor control; mouse model; multisystem proteinopathy; muscular system; mutant; prion-like; programs; protein TDP-43; protein aggregation; rare variant; response; tau Proteins; therapeutic target; trafficking; transcription factor; valosin containing protein mutation

The overarching goal of R01 renewal is to continue our work on a multisystem degenerative disorder with muscle weakness and fronto-temporal dementia. VCP pathologies are unified by ubiquitin and TDP43 inclusions. VCP disease mutations affect multiple cellular process such as autophagy and endolysosomal trafficking that converge at the lysosome. Recently we have identified a critical role for VCP in maintaining lysosome integrity that is impaired in the setting of disease mutatins. We plan to perform the following aims will 1) Evaluate the role of VCP in lysophagy in neurons and muscle; 2) Evaluate lysosome mediated signaling pathways such as mTORC1 and TFEB in the brains of mice with VCP disease mutations; 3) Explore the role of VCP in the endolysosomal escape of proteopathic seeds. Upon completion we will understand the role of VCP in lysosomal homeostasis and how this is affected by VCP disease mutations in muscle and neurons.

R 01更新的首要目标是继续我们在多系统退化方面的工作， 肌肉无力和额颞叶痴呆症。VCP的病理学是统一的， 泛素和TDP 43包涵体。VCP疾病突变影响多种细胞过程，例如 自噬和内溶酶体运输在溶酶体处汇合。最近我们 确定了VCP在维持溶酶体完整性方面的关键作用， 疾病突变我们计划执行以下目标：1）评估VCP在以下方面的作用： 2）评估溶酶体介导的信号传导途径，例如 mTORC 1和TFEB在VCP疾病突变小鼠脑中的作用; 3）探索mTORC 1和TFEB在VCP疾病突变小鼠脑中的作用。 VCP在蛋白质病种子的内溶酶体逃逸中的作用完成后，我们将了解 VCP在溶酶体稳态中的作用以及VCP疾病突变如何影响溶酶体稳态， 肌肉和神经元。