AAA ATPase p97/VCP and Inclusion Body Myopathy

AAA ATPase p97/VCP 与包涵体肌病

• 批准号: 7644962
• 负责人: CONRAD C WEIHL
• 金额: $ 15.28万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7644962
• 关键词: ATP phosphohydrolase; Address; Affect; Aging; Animal Model; Biopsy; Cell physiology; Cells; Characteristics; Chimeric Proteins; Clinical; Degradation Pathway; Detergents; Disease; Doctor of Philosophy; Endoplasmic Reticulum Degradation Pathway; Environment; Experimental Designs; Fostering; Frontotemporal Dementia; Future; Goals; Half-Life; Histopathology; Human Pathology; Immunoblotting; Immunofluorescence Immunologic; Inclusion Bodies; Inclusion Body Myositis; Inherited; Lead; Mentors; Missense Mutation; Modeling; Molecular; Morbidity - disease rate; Muscle; Muscle Cells; Muscle Weakness; Mutation; Myoblasts; Myopathy; Nature; Neurologist; Paget' s Disease; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Property; Protein Conformation; Proteins; Recombinants; Research Personnel; Role; Scientist; Skeletal Muscle; Structure; Syndrome; Testing; Tissues; Training; Transgenic Mice; Ubiquitin; age related; aged; career; clinical phenotype; cofactor; effective therapy; enzyme activity; insight; mortality; multicatalytic endopeptidase complex; mutant; p97 ATPase; p97-VCP protein; programs; protein aggregate; protein aggregation; protein degradation; therapeutic target

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.

描述（由申请人提供）：候选人是一位经过医学博士/博士学位培训的临床神经科医生，其职业目标是利用包涵体肌炎（IBM）作为典型疾病，研究与骨骼肌疾病相关的衰老细胞机制。受指导的科学培训将在博士的实验室中联合进行。艾伦·佩斯特罗克和菲利斯·汉森。这两位不同科学家的合并营造了一个让候选人成为独立调查员的环境。 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，并且没有有效的治疗方法。 p97/VCP 的错义突变会导致常染色体显性遗传综合征 HIBM、佩吉特氏病和额颞叶痴呆 (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（特别是泛素蛋白酶体途径）中具有明显的作用。在拟议项目中要测试的中心假设如下：1）p97/VCP 中的 IBMPFD 突变导致蛋白质聚集； 2) IBMPFD 突变体 p97/VCP 聚集体影响细胞蛋白的降解，并导致 IBM 和 HIBM 患病肌肉中细胞质、泛素阳性内含物的特征性组织病理学特征； 3）了解HIBM的分子机制将阐明IBM和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）纯化重组p97/VCP蛋白以评估结构和酶活性； 2) 培养表达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； 3) 表达家族突变体 p97/VCP-R155H 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 疾病发病机制所涉及的分子和细胞机制，对于确定未来的治疗靶点至关重要。

项目成果

TDP-43 accumulation in inclusion body myopathy muscle suggests a common pathogenic mechanism with frontotemporal dementia.

• DOI: 10.1136/jnnp.2007.131334
• 发表时间: 2008-10
• 期刊: Journal of neurology, neurosurgery, and psychiatry
• 作者: Weihl CC;Temiz P;Miller SE;Watts G;Smith C;Forman M;Hanson PI;Kimonis V;Pestronk A
• 通讯作者: Pestronk A