The AR N/C interaction in SBMA - Mechanistic role and therapeutic potential

项目总结： 许多神经退行性疾病，包括阿尔茨海默氏症、帕金森氏病和 多发性谷氨酰胺病，是由于多种基因导致蛋白质错误折叠和堆积所致 和/或环境原因。脊髓和延髓肌萎缩症(SBMA)是一种成人起病的遗传性疾病。 由雄激素受体(AR)内的多聚谷氨酰胺膨胀引起的神经肌肉疾病； 它与聚谷氨酰胺扩张引起的其他神经退行性疾病有关，包括 亨廷顿氏病和几个脊髓小脑性共济失调。尽管通往地球的准确路径 神经元功能障碍和死亡未知，转基因小鼠和细胞模型的评估 这些疾病已经对疾病的发病机制产生了深刻的认识。SBMA与 其他多谷氨酰胺疾病，其发生和发展依赖于AR雄激素 配基。我们的细胞和小鼠SBMA模型复制了雄激素和多谷氨酰胺依赖的 在患者中看到的核AR聚集以及由此产生的毒性，使这些模型 对于分析与AR毒性有关的上游事件的机理基础非常有用。我们的 长期目标是使用这些模型来发展对步骤的机械性理解 在SBMA发病机制中，对激素结合作出反应，并发展治疗 基于这一理解的方法。我们之前的研究表明，一种特定的 激素结合时AR的构象状态，即N/C相互作用，是 其聚集和毒性；抑制N/C相互作用在体外和体内都具有保护作用 模特们。此外，我们发现Ser-16的磷酸化是这种保护所必需的。我们建议 在此应用程序中进一步了解AR N/C两者的潜在作用机制 相互作用和Ser-16在疾病中的磷酸化。此外，我们还建议筛选选择性AR 调节剂(SARM)可阻止AR N/C相互作用，从而在SBMA发病机制中发挥作用。 在体外和体内都有。我们预计，这些研究的结果将把我们引向一个新的 认识SBMA的分子发病机制促进我国新型药物的开发 针对SBMA的治疗。

Project Summary: Many neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease and the polyglutamine diseases, result from protein misfolding and accumulation due to a variety of 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 pathway leading to neuronal dysfunction and death is unknown, the evaluation of transgenic mouse and cell models of these diseases has yielded mechanistic insights to 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 steps in SBMA pathogenesis that occur in response to hormone binding and to develop therapeutic approaches based on that understanding. Our previous studies revealed that a specific conformational state of the AR that occurs upon hormone binding, the N/C interaction, is required for its aggregation and toxicity; inhibition of the N/C interaction is protective in both in vitro and in vivo models. Moreover, we found that Ser-16 phosphorylation is required for this protection. We propose in this application to further understand the mechanism underlying the role of both the AR N/C interaction and Ser-16 phosphorylation in disease. In addition, we propose to screen selective AR modulators (SARMs) that prevent the AR N/C interaction for their effects on SBMA pathogenesis, both in vitro and in vivo. 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.