AUTOPHAGIC DYSFUNCTION IN IBMPFD ASSOCIATED MUSCLE DISEASE

IBMPFD 相关肌肉疾病中的自噬功能障碍

• 批准号: 8441399
• 负责人: CONRAD C WEIHL
• 金额: $ 13.42万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-30 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8441399
• 关键词: Affect; Age; Aging; Architecture; Area; Autophagocytosis; Autophagosome; Award; Binding; Biological Assay; Cells; Clinical; Collaborations; Complex; Cultured Cells; Data; Defect; Degenerative Disorder; Degradation Pathway; Dementia; Disease; Fluorescent Dyes; Free Will; Functional disorder; Future; General Population; Goals; Image; Impairment; Inclusion Bodies; Inclusion Body Myositis; Independent Scientist Award; Laboratories; Learning; Life; Lysosomes; Mammalian Cell; Mass Spectrum Analysis; Measures; Mediating; Mediation; Mus; Muscle Weakness; Mutation; Myopathy; Osteitis Deformans; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Physicians; Process; Proteins; Research; Role; Scientist; Skeletal Muscle; Small Interfering RNA; Sorting - Cell Movement; Sporadic Inclusion Body Myopathy; System; Techniques; Time; Tissues; Transgenic Mice; Ubiquitin; Ubiquitinated Protein Degradation; Vacuole; Yeasts; age related; aged; career; career development; cofactor; forging; histone deacetylase 6; in vivo; insight; interest; lysosomal proteins; multicatalytic endopeptidase complex; mutant; novel; programs; protein complex; protein degradation; protein function; tool; trafficking; valosin-containing protein

DESCRIPTION (provided by applicant): The applicant is a physician-scientist with an interest in age associated muscle disorders. This award will free him from clinical duties, allow him to focus on research and become a leader in the field. One age associated muscle disorder is due to mutations in valosin containing protein (VCP) which causes IBMPFD or inclusion body myopathy (IBM) associated with Paget's disease of the bone (PDB) and fronto-temporal dementia (FTD). Muscle weakness is the most prevalent phenotypic feature. Although IBMPFD itself is rare, each component (IBM, PDB and FTD) is exceedingly common in the general population. VCP mutations disrupt autophagosome maturation resulting in dysfunctional autophagy and muscle weakness. We propose to evaluate 1) Autophagosome maturation in skeletal muscle; 2) Characterize a novel VCP complex necessary for the autophagic degradation of ubiquitinated proteins. 3) Evaluate the role of VCP and its cofactors on autophagosome maturation. The applicant will learn new techniques, forge new collaborations and develop a research program in his lab to understand the interplay between protein degradation pathways in age muscle disease. The K02 award mechanism will allow the applicant to focus full time on research and become a leader in the field. PUBLIC HEALTH RELEVANCE: Pathologic protein inclusions accumulate in many divergent disease states associated with aging like inclusion body myositis and dementia. We hypothesis that an impairment in autophagy conferred by mutations in the protein VCP result in inclusion body myopathy associated with paget's disease of the bone and fronto-temporal dementia (IBMPFD). Understanding IBMPFD will lend insight into the treatment of other more common age related disorders.

描述（由申请人提供）：申请人是一名对年龄相关肌肉疾病感兴趣的内科科学家。该奖项将使他从临床工作中解脱出来，使他能够专注于研究，并成为该领域的领导者。一种与年龄相关的肌肉疾病是由于含有缬素蛋白（VCP）的突变引起IBMPFD或包涵体肌病（IBM），与佩吉特骨病（PDB）和额颞叶痴呆（FTD）相关。肌无力是最普遍的表型特征。尽管IBMPFD本身很少见，但每个组件（IBM、PDB和FTD）在一般人群中非常常见。VCP突变破坏自噬体成熟，导致自噬功能失调和肌肉无力。我们建议评估1)骨骼肌中自噬体的成熟；2)表征泛素化蛋白自噬降解所必需的新型VCP复合物。3)评价VCP及其辅助因子在自噬体成熟中的作用。申请人将学习新技术，建立新的合作关系，并在他的实验室开展研究项目，以了解老年肌肉疾病中蛋白质降解途径之间的相互作用。K02奖励机制将允许申请人专注于研究，并成为该领域的领导者。