AAA ATPase p97/VCP and Inclusion Body Myopathy

描述（由申请人提供）：候选人是一名医学博士/博士训练的临床神经学家，其职业目标是研究与骨骼肌疾病相关的衰老细胞机制，以包体体肌炎（IBM）为原型疾病。指导的科学训练将在博士实验室共同进行。Alan Pestronk和Phyllis Hanson。这两位不同的科学家的合并营造了一种环境，使候选人能够成为一名独立的研究者。IBM和遗传性包涵体肌病（HIBM）影响老年患者，发病率和死亡率高，且无有效治疗方法。p97/VCP错义突变可导致常染色体显性综合征（HIBM）、Paget病和额颞叶痴呆（IBMPFD）。P97/VCP是一种AAA atp酶（atp酶与其他细胞活性相关），在蛋白质降解，特别是泛素-蛋白酶体途径中具有明确的作用。该项目拟验证的中心假设如下：1)p97/VCP中的IBMPFD突变导致该蛋白聚集；2) IBMPFD突变体p97/VCP聚集体影响细胞蛋白的降解，并负责IBM和IBM病变肌肉中细胞质，泛素阳性包涵体的特征性组织病理学；3)了解IBM的分子机制将有助于阐明IBM及其他衰老相关疾病的发病机制。候选人将测试这些

DESCRIPTION (provided by applicant): The candidate is an MD/PhD trained clinical neurologist with a career goal to investigate the cellular mechanisms of aging in relation to skeletal muscle disorders, using inclusion body myositis (IBM) as a prototypical disease. The mentored scientific training will be performed jointly in the labs of Drs. Alan Pestronk and Phyllis Hanson. The merger of these two diverse scientists fosters an environment that will allow the candidate to become an independent investigator. IBM and hereditary inclusion body myopathy (HIBM) affect aged patients, cause significant morbidity and mortality and have no effective treatment. Missense mutations in p97/VCP cause the autosomal dominantly syndrome HIBM, Paget's Disease and frontotemporal dementia (IBMPFD). P97/VCP is a AAA ATPase (ATPase Associated with other cellular Activities) and has a clear role in protein degradation, in particular the ubiquitin-proteasome pathway. The central hypotheses to be tested during the proposed project are the following: 1) IBMPFD mutations in p97/VCP cause the protein to aggregate; 2) IBMPFD mutant p97/VCP aggregates affect the degradation of cellular proteins and are responsible for the characteristic histopathology of cytoplasmic, ubiquitin positive inclusions seen in IBM and HIBM diseased muscle; 3) An understanding of the molecular mechanism of HIBM will elucidate the pathogenesis of IBM and other aging related diseases. The candidate will test these hypotheses using the following experimental designs: 1) Purified recombinant p97/VCP protein to evaluate structure and enzyme activity; 2) Cultured myoblasts expressing p97/VCP proteins to evaluate cellular degradative pathways and the proteins affected; and 3) Transgenic mice expressing familial mutant p97/VCP-R155H to model the pathologic and clinical aspects of HIBM. These studies will lend insight into the molecular and cellular mechanisms involved in IBM disease pathogenesis and are critical for identifying future therapeutic targets.