Pathways of Neurodegeneration in SBMA

描述（由申请方提供）：拟定研究的长期目标是开发有效治疗脊髓延髓肌萎缩症（SBMA）的方法，SBMA是一种由雄激素受体（AR）中多聚谷氨酰胺（polyQ）束扩张引起的神经退行性疾病。我的实验室最近发表了令人信服的证据，表明雄激素受体的天然功能是毒性的重要介质。具体而言，我们使用果蝇遗传学和功能基因组学的组合，了解到AR的AF-2结构域与核激素共调节蛋白的相互作用是发病机制中的一个重要步骤。这一令人兴奋的发现表明，用现有的抗雄激素疗法调节天然AR功能可能有效治疗这种毁灭性的神经退行性疾病。接下来的关键步骤是在SBMA的哺乳动物模型中证实这种发病机制，并进一步阐明受多聚谷氨酰胺扩增干扰的特定AR功能，如所附建议中所述。一个相关的问题是确定治疗中要靶向的运动单位的最重要组成部分：运动神经元或肌肉。为此目的，我们已开始进行实验，以实现三个具体目标。首先，我们已经产生了一系列新的转基因小鼠，有条件地表达野生型或突变形式的人雄激素受体，以证实这些发现在哺乳动物模型。其次，我们将追求蛋白质组学的方法来表征多聚谷氨酰胺扩增如何影响雄激素受体的天然相互作用。第三，我们将专门在运动神经元或肌肉中设计条件表达，以衡量这些组织对SBMA小鼠退行性表型的相对贡献。

DESCRIPTION (provided by applicant): The long term goal of the proposed research is to develop effective treatment for spinobulbar muscular atrophy (SBMA), a neurodegenerative disease caused by expansion of a polyglutamine (polyQ) tract in the androgen receptor (AR). My laboratory has recently published compelling evidence that native functions of the androgen receptor are essential mediators of toxicity. Specifically, we used a combination of Drosophila genetics and functional genomics to learn that interaction of the AF-2 domain of AR with nuclear hormone co-regulatory protein is an essential step in pathogenesis. This exciting finding suggests that modulation of native AR function with existing anti-androgen therapies may be effective in the treatment of this devastating neurodegenerative disease. The critical next steps are corroboration of this mechanism of pathogenesis in a mammalian model of SBMA and further elucidation of the specific AR functions that are perturbed by polyglutamine expansion, as outlined in the accompanying proposal. A related question is determination of the most important component of the motor unit to be targeted in therapy: motor neuron or muscle. Toward that end we have initiated experiments to address three specific aims. First, we have generated a novel series of transgenic mice that conditionally express wild type or mutant forms of human androgen receptor to corroborate these findings in a mammalian model. Second, we will pursue proteomic approaches to characterize how polyglutamine expansion influences native interactions of the androgen receptor. Third, we will engineer conditional expression exclusively in motor neuron or muscle to gauge the relative contributions of these tissues to the degenerative phenotype in SBMA mice.