The Role of the AR N/C Interaction in SMBA

AR N/C 交互在 SMBA 中的作用

• 批准号: 8664458
• 负责人: DIANE E MERRY
• 金额: $ 33.57万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8664458
• 关键词: Adult; Alzheimer' s Disease; Amyotrophic Lateral Sclerosis; Androgen Receptor; Androgens; Animal Model; Behavior; Binding; Biochemical; C-terminal; Cell Nucleus; Cell model; Cessation of life; DNA Binding; Development; Disease; Evaluation; Event; Family; Fluorescence Resonance Energy Transfer; Genetic; Goals; Half-Life; Hormones; Huntington Disease; Image; Imaging Techniques; Intervention; Label; Lead; Metabolism; Modeling; Modification; Molecular; Molecular Conformation; Motor Neurons; Mutation; Neurodegenerative Disorders; Neuromuscular Diseases; Neuronal Dysfunction; Nuclear; Nuclear Export; PC12 Cells; Parkinson Disease; Pathogenesis; Pathology; Pathway interactions; Phosphorylation; Play; Post-Translational Protein Processing; Property; Proteolysis; Receptor Aggregation; Regulation; Role; Series; Symptoms; Techniques; Testing; Toxic effect; Transgenic Mice; Transgenic Organisms; Two-Hybrid System Techniques; Work; base; cofactor; improved; in vivo; mouse model; mutant; neuropathology; novel; novel therapeutics; polyglutamine; protein misfolding; receptor; research study; spinal and bulbar muscular atrophy; therapeutic development; therapeutic target; trafficking

DESCRIPTION (provided by applicant): Many neurodegenerative diseases, including spinal and bulbar muscular atrophy (SBMA) and ALS, result from protein misfolding and accumulation due to a variety of both genetic and environmental causes. SBMA is an adult-onset neuromuscular disease that is caused by polyglutamine expansion within the androgen receptor (AR); it is related mechanistically to other neurodegenerative diseases caused by polyglutamine expansion. Although the precise pathway leading to neuronal dysfunction and death is unknown, the evaluation of transgenic mouse and cell models of these diseases has yielded many mechanistic clues. Our transgenic cell and mouse models of SBMA reproduce the proximate events of polyglutamine-dependent proteolysis and nuclear aggregation, making these models highly useful for the analysis of the mechanistic basis for these upstream events. SBMA stands apart from other polyglutamine diseases in that its onset and progression are androgen- dependent. Our preliminary studies in cell models of SBMA indicate that a structural change in the AR that occurs upon androgen binding and that involves an interdomain interaction between the amino- (N-) and carboxyl- (C-) terminal regions is required for mutant AR aggregation and toxicity. Our long- term objectives are to use our transgenic mouse and cell models to determine the role of the N/C interaction in vivo and to develop a mechanistic understanding for this role. We predict that these studies will reveal further details about the step or steps in AR trafficking and metabolism that are derailed by the polyglutamine expansion. To reach these goals, we propose three specific aims: 1) To evaluate the effect of polyglutamine expansion on the AR N/C interaction, using both imaging and biochemical approaches; 2) To determine the role of the AR N/C interaction in a mouse model of SBMA; 3) To determine the mechanistic basis by which the N/C interaction impacts polyglutamine- expanded AR metabolism. We anticipate that results from these studies will lead us to a new understanding of the molecular pathogenesis of SBMA and enhance our development of new therapies for SBMA.

描述（由申请人提供）：许多神经退行性疾病，包括脊髓和延髓肌萎缩症（SBMA）和ALS，是由多种遗传和环境原因引起的蛋白质错误折叠和积累引起的。SBMA是由雄激素受体（AR）内的多聚谷氨酰胺扩增引起的成人发作性神经肌肉疾病;它与多聚谷氨酰胺扩增引起的其他神经退行性疾病在机制上相关。虽然导致神经元功能障碍和死亡的确切途径尚不清楚，但对这些疾病的转基因小鼠和细胞模型的评估已经产生了许多机制线索。我们的转基因细胞和SBMA小鼠模型再现了聚谷氨酰胺依赖性蛋白水解和核聚集的近似事件，使得这些模型对于分析这些上游事件的机制基础非常有用。SBMA与其他多聚谷氨酰胺疾病的区别在于其发病和进展是雄激素依赖性的。我们在SBMA细胞模型中的初步研究表明，雄激素结合后发生的AR结构变化，涉及氨基（N-）和羧基（C-）末端区域之间的结构域相互作用，是突变体AR聚集和毒性所必需的。我们的长期目标是使用我们的转基因小鼠和细胞模型来确定N/C相互作用在体内的作用，并发展对这种作用的机制理解。我们预测，这些研究将揭示更多关于AR运输和代谢中被多聚谷氨酰胺扩增破坏的步骤的细节。为了实现这些目标，我们提出了三个具体目标：1）使用成像和生化方法评估多聚谷氨酰胺扩展对AR N/C相互作用的影响; 2）确定AR N/C相互作用在SBMA小鼠模型中的作用; 3）确定N/C相互作用影响多聚谷氨酰胺扩展AR代谢的机制基础。我们预计，这些研究的结果将使我们对SBMA的分子发病机制有新的认识，并促进我们对SBMA新疗法的开发。