The Role of the AR Interactome in SBMA

AR Interactome 在 SBMA 中的作用

基本信息

批准号：
10112972
负责人：
DIANE E MERRY
金额：
$ 42.93万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-05-15 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10112972
关键词：
Acetylation Adult Alzheimer&apos s Disease Amino Acids Amyotrophic Lateral Sclerosis Androgen Receptor Androgens Animal Model Arginine Binding Biochemical Brain Stem Cell Culture Techniques Cell Death Cell Nucleus Cell model Cell physiology Cells Consensus Disease Disease model Evaluation Event Family Functional disorder Genetic Hormones Huntington Disease Inclusion Bodies Inherited Investigation Knock-in Knock-in Mouse Knowledge Lead Length Ligands Link Lysine Metabolism Methylation Modeling Molecular Molecular Conformation Motor Neurons Mus Muscle Muscle Cells Muscular Atrophy Neurodegenerative Disorders Neuromuscular Diseases Neuronal Dysfunction Nuclear Nuclear Inclusion Onset of illness Parkinson Disease Pathogenesis Pathogenicity Pathology Pathway interactions Patients Phosphorylation Post-Translational Protein Processing Protein Conformation Proteins Proteolysis Proteomics RIPK1 gene Receptor Aggregation Role Serine Signs and Symptoms Site Spinal Cord Spinal Diseases Spinocerebellar Ataxias Stable Isotope Labeling Structure Sum Therapeutic Tissues Toxic effect Transgenic Mice androgenic base genetic approach in vivo induced pluripotent stem cell insight mouse model mutant neuromuscular neuron loss new therapeutic target novel polyglutamine protein aggregation protein misfolding protein protein interaction public health relevance receptor receptor function small molecule spinal and bulbar muscular atrophy therapeutic development

项目摘要

Project Summary: Several neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, as well as the polyglutamine expansion diseases, result from protein misfolding and accumulation due to genetic and/or environmental causes. Spinal and bulbar muscular atrophy (SBMA) is an adult-onset, inherited neuromuscular disease that is caused by polyglutamine expansion within the androgen receptor (AR); it is related to other neurodegenerative diseases caused by polyglutamine expansion, including Huntington's disease and several spinocerebellar ataxias. Although the precise pathways leading to neuronal dysfunction and death are unknown, the evaluation of transgenic mouse and cell models of these diseases has yielded mechanistic insights into disease pathogenesis. SBMA stands apart from other polyglutamine diseases in that its onset and progression are dependent on AR androgenic ligands. Our cell and mouse models of SBMA reproduce the androgen- and polyglutamine-dependent nuclear AR aggregation seen in patients, as well as its consequent toxicity, making these models highly useful for the analysis of the mechanistic basis for upstream events involved in AR toxicity. Our long-term objectives are to use these models to develop a mechanistic understanding of hormone-dependent, polyglutamine-expanded AR toxicity. A growing body of evidence suggests that long polyQ tracts cause cellular dysfunction and ultimately cell death, at least in part by dysregulating protein-protein interactions that sustain normal cellular function. We have utilized a quantitative proteomics approach to identify changes in the AR protein interaction network caused by polyQ expansion in a cell model, and identified several protein candidates that may be involved in polyQ-expanded AR pathogenicity. Our preliminary studies on one of the identified interactors, USP7 (a preferential interactor with polyQ-expanded AR), reveals a role for USP7 in SBMA. We propose here to 1) carry out additional interactome screens in spinal cord and muscle tissues of a validated mouse model of SBMA, 2) investigate the roles of the other differentially interacting proteins identified in our initial screen, and 3) continue our mechanistic studies of the role of USP7 in SBMA. We anticipate that results from these studies will lead us to a deeper understanding of the molecular pathogenesis of SBMA, and will yield novel pathways amenable to therapeutic modulation for SBMA.

项目概要：多种神经退行性疾病，包括阿尔茨海默病、帕金森病以及多聚谷氨酰胺扩张疾病，是由遗传性蛋白质错误折叠和积累引起的和/或环境原因。脊髓和延髓肌萎缩症 (SBMA) 是一种成人发病的遗传性由雄激素受体 (AR) 内的聚谷氨酰胺扩张引起的神经肌肉疾病；它与多聚谷氨酰胺扩张引起的其他神经退行性疾病有关，包括亨廷顿舞蹈症和几种脊髓小脑性共济失调。尽管精确的路径导致神经元功能障碍和死亡尚不清楚，转基因小鼠和细胞模型的评估这些疾病使人们对疾病发病机制有了深入的了解。 SBMA 与众不同其他多聚谷氨酰胺疾病，其发病和进展依赖于 AR 雄激素配体。我们的 SBMA 细胞和小鼠模型再现了雄激素和多谷氨酰胺依赖性在患者体内观察到的核 AR 聚集及其随之而来的毒性，使这些模型成为可能对于分析 AR 毒性相关上游事件的机制基础非常有用。我们的长期目标是使用这些模型来建立对激素依赖性、多聚谷氨酰胺扩展的 AR 毒性。越来越多的证据表明长的polyQ束会导致细胞功能障碍并最终导致细胞死亡，至少部分是由于维持正常细胞功能的蛋白质-蛋白质相互作用失调。我们利用了一个定量蛋白质组学方法来识别 AR 蛋白质相互作用网络的变化 PolyQ 在细胞模型中的扩展，并鉴定了几种可能参与的候选蛋白质 PolyQ 扩展的 AR 致病性。我们对已确定的相互作用者之一 USP7 的初步研究（与 PolyQ 扩展的 AR 的优先相互作用子）揭示了 USP7 在 SBMA 中的作用。我们建议 1) 在经过验证的脊髓和肌肉组织中进行额外的相互作用组筛选 SBMA 小鼠模型，2) 研究已识别的其他差异相互作用蛋白的作用在我们的初始筛选中，3) 继续我们对 USP7 在 SBMA 中的作用的机制研究。我们预计这些研究的结果将引导我们更深入地了解分子 SBMA 的发病机制，并将产生适合 SBMA 治疗调节的新途径。