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/博士培训的临床神经学家，其职业目标是研究与骨骼肌疾病相关的衰老细胞机制，使用包涵体肌炎（IBM）作为原型疾病。指导科学培训将在Alan Pestronk和Phyllis Hanson博士的实验室联合进行。这两个不同的科学家的合并培养了一个环境，使候选人成为一个独立的调查员。IBM和遗传性包涵体肌病（HIBM）影响老年患者，导致显着的发病率和死亡率，并没有有效的治疗。p97/VCP的错义突变导致常染色体显性遗传综合征HIBM、佩吉特病和额颞叶痴呆（IBMPFD）。P97/VCP是一种AAA ATP酶（与其他细胞活动相关的ATP酶），在蛋白质降解中具有明确的作用，特别是泛素-蛋白酶体途径。在所提出的项目期间要检验的中心假设如下：1）p97/VCP中的IBMPFD突变引起蛋白质聚集; 2）IBMPFD突变体p97/VCP聚集体影响细胞蛋白质的降解，并负责在IBM和HIBM患病肌肉中观察到的细胞质、泛素阳性包涵体的特征性组织病理学; 3）对HIBM分子机制的认识将有助于阐明IBM及其他衰老相关疾病的发病机制。候选人将测试这些 使用以下实验设计进行假设：1）纯化的重组p97/VCP蛋白以评估结构和酶活性; 2）培养的表达p97/VCP蛋白的成肌细胞以评估细胞降解途径和受影响的蛋白;和3）表达家族性突变体p97/VCP-R155 H的转基因小鼠以模拟HIBM的病理和临床方面。这些研究将有助于深入了解IBM疾病发病机制中涉及的分子和细胞机制，并对确定未来的治疗靶点至关重要。

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.