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，包括脊柱和鳞茎肌肉萎缩（SBMA）和ALS，是由于蛋白质折叠和积累而导致的，这是由于各种遗传和环境原因引起的。 SBMA是一种成年神经肌肉疾病，是由雄激素受体（AR）内的聚谷氨酰胺扩张引起的；它与多谷氨酰胺扩张引起的其他神经退行性疾病机械上有关。尽管导致神经元功能障碍和死亡的精确途径尚不清楚，但这些疾病的转基因小鼠和细胞模型的评估产生了许多机械线索。我们的SBMA的转基因细胞和小鼠模型重现了多谷氨酰胺依赖性蛋白水解和核聚集的近端事件，这使得这些模型对于分析这些上游事件的机械基础非常有用。 SBMA与其他聚谷氨酰胺疾病不同，因为其发作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，AR的结构变化在雄激素结合后发生，并且涉及突变AR聚集和毒性的氨基（N-）和羧基（n-）和羧基（c-）末端之间的域间相互作用。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，并对该作用发展机械理解。我们预测，这些研究将揭示有关聚谷氨酰胺扩张脱轨的AR运输和代谢的步骤或步骤的更多细节。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相互作用影响多谷氨酰胺扩展的AR代谢的机理基础。我们预计这些研究的结果将使我们对SBMA的分子发病机理有了新的了解，并增强了我们针对SBMA的新疗法的发展。