AUTOPHAGIC DYSFUNCTION IN IBMPFD ASSOCIATED MUSCLE DISEASE

IBMPFD 相关肌肉疾病中的自噬功能障碍

基本信息

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
项目类别：
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

项目摘要

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）：申请人是一位对年龄相关肌肉疾病感兴趣的医师科学家。该奖项将使他摆脱临床职责，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洛新蛋白 (VCP) 的突变引起的，该突变会导致 IBMPFD 或与佩吉特骨病 (PDB) 和额颞叶痴呆 (FTD) 相关的包涵体肌病 (IBM)。肌肉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）在普通人群中都非常常见。 VCP 突变破坏自噬体成熟，导致自噬功能障碍和肌肉无力。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)评估VCP及其辅助因子对自噬体成熟的作用。申请人将学习新技术，建立新的合作，并在他的实验室开发一个研究项目，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奖励机制将让申请者能够全职专注于研究并成为该领域的领导者。公共卫生相关性：病理性蛋白质内含物在许多与衰老相关的不同疾病状态中积累，如包涵体肌炎和痴呆。我们假设，VCP 蛋白突变导致的自噬损伤会导致与佩吉特骨病和额颞叶痴呆 (IBMPFD) 相关的包涵体肌病。了解 IBMPFD 将有助于深入了解其他更常见的年龄相关疾病的治疗。