AUTOPHAGIC DYSFUNCTION IN IBMPFD ASSOCIATED MUSCLE DISEASE

描述（由申请人提供）：申请人是一名对年龄相关性肌肉疾病感兴趣的医生-科学家。该奖项将使他从临床职责中解脱出来，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缬沙宁蛋白（VCP）的突变，其引起与骨的佩吉特病（PDB）和额颞痴呆（FTD）相关的IBMPFD或包涵体肌病（IBM）。肌无力是最普遍的表型特征。虽然IBMPFD本身是罕见的，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，导致功能失调的自噬和肌肉无力。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，以了解蛋白质降解途径在老年肌肉疾病中的相互作用。K 02奖励机制将允许申请人全职专注于研究，并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.