AUTOPHAGIC DYSFUNCTION IN IBMPFD ASSOCIATED MUSCLE DISEASE

描述(由申请人提供)：申请人是一位对年龄相关性肌肉疾病感兴趣的内科科学家。这一奖项将把他从临床职责中解放出来，让他专注于研究，成为该领域的领导者。一种年龄相关性肌肉疾病是由于含有Valosin的蛋白(VCP)的突变导致IBMPFD或与Paget‘s病(PDB)和额颞痴呆(FTD)相关的包涵体肌病(IBM)。肌肉无力是最常见的表型特征。尽管IBMPFD本身很少见，但每个组件(IBM、PDB和FTD)在普通人群中非常常见。VCP突变破坏了自噬小体的成熟，导致自噬功能障碍和肌肉无力。我们建议评估1)骨骼肌中自噬小体的成熟；2)表征泛素化蛋白自噬降解所必需的新的VCP复合体。3)评价VCP及其辅助因子在自噬小体成熟中的作用。申请者将学习新技术，建立新的合作，并在他的实验室开发一个研究计划，以了解蛋白质降解途径在老年肌肉疾病中的相互作用。K02奖励机制将使申请者能够全身心地专注于研究，成为该领域的领导者。

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.