Inhibiting the Androgen Receptor N/C Interaction to Treat 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聚集的近似事件，使得这些模型对于分析影响这些上游事件的新治疗途径非常有用。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评估防止AR N/C相互作用的新型AR配体的治疗功效。我们预测，这些研究将揭示这些配体中哪一种最有效的细节，并使我们能够进一步开发用于治疗干预的配体亚类。为了达到这些目标，我们提出了两个具体的目标：1）评估SARM的效力，防止N/C相互作用在调节AR聚集和毒性在两个细胞模型的SBMA，并评估突变体AR的转录功能后，SARM结合; 2）进行临床前测试的最有效的SARM在我们的转基因小鼠模型的SBMA。我们预计，这些研究的结果将引导我们找到SBMA的新疗法，并为其他多聚谷氨酰胺疾病打开一扇新的研究之门。 公共卫生相关性：多聚谷氨酰胺疾病代表以蛋白质错误折叠和积累为特征的神经变性疾病的较大家族;这些疾病包括阿尔茨海默病、亨廷顿病、帕金森病和肌萎缩侧索硬化症（ALS）。我们正在开发一种治疗策略，旨在防止突变蛋白的异常折叠和积累，这代表了致病途径中的上游事件。本文提出的研究将测试与突变蛋白结合的新型治疗化合物，允许其正常功能，但防止形成毒性构象;如果成功，这种策略也应该与其他神经退行性疾病相关。

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 have yielded many mechanistic clues. Our transgenic cell and mouse models of SBMA reproduce the proximate events of polyglutamine-dependent proteolysis and aggregation, making these models highly useful for the analysis of novel therapeutic avenues that affect these upstream events. SBMA stands apart from other polyglutamine diseases in that its onset and progression are androgen- dependent. Our preliminary studies in our 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 evaluate the therapeutic efficacy of novel AR ligands that prevent the AR N/C interaction. We predict that these studies will reveal the details of which of these ligands is most effective and allow us to further develop this subclass of ligands for therapeutic intervention. To reach these goals, we propose two specific aims: 1) To evaluate the efficacy of SARMs that prevent the N/C interaction in modulating AR aggregation and toxicity in two cell models of SBMA, and to evaluate the transcriptional function of the mutant AR upon SARM binding; 2) To carry out preclinical testing of the most effective SARMs in our transgenic mouse model of SBMA. We anticipate that results from these studies will lead us to new therapies for SBMA and will open a novel investigational door for other polyglutamine diseases as well. PUBLIC HEALTH RELEVANCE: Polyglutamine diseases represent a larger family of neurodegenerative diseases characterized by protein misfolding and accumulation; these diseases include Alzheimer's disease, Huntington's disease, Parkinson's disease and amyotrophic lateral sclerosis (ALS). We are developing a therapeutic strategy designed to prevent the abnormal folding and accumulation of mutant protein, which represents an upstream event in the pathogenic pathway. The studies proposed here will test novel therapeutic compounds that bind to the mutant protein, allow its normal function, but prevent the formation of a toxic conformation; this strategy, if successful, should also be relevant to other neurodegenerative diseases.