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，包括脊髓和球性肌萎缩症（SBMA）和ALS，是由各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是一种成人发病的神经肌肉疾病，由雄激素受体（AR）内的聚谷氨酰胺扩张引起；它与聚谷氨酰胺扩张引起的其他神经退行性疾病有机制关系。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提供了许多机制线索。我们的转基因细胞和小鼠SBMA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，使这些模型对分析影响这些上游事件的新治疗途径非常有用。SBMA与其他多谷氨酰胺疾病不同，它的发病和进展依赖于雄激素。我们对SBMA细胞模型的初步研究表明，突变AR聚集和毒性需要在雄激素结合时发生AR的结构变化，并且涉及氨基（N-）和羧基（C-）末端区域之间的结构域间相互作用。我们的长期目标是利用我们的转基因小鼠和细胞模型来评估阻止AR N/C相互作用的新型AR配体的治疗效果。我们预测，这些研究将揭示哪些配体是最有效的细节，并允许我们进一步开发这类配体用于治疗干预。为了达到这些目标，我们提出了两个具体的目标：1)在SBMA的两种细胞模型中，评估阻止N/C相互作用的SARMs在调节AR聚集和毒性方面的功效，并评估SARM结合突变AR的转录功能；2)在我们的SBMA转基因小鼠模型中对最有效的SARMs进行临床前试验。我们预计这些研究的结果将引导我们开发SBMA的新疗法，并为其他多聚谷氨酰胺疾病的研究打开新的大门。

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.