Pathways of Neurodegeneration in SBMA

描述（由申请人提供）：拟议研究的长期目标是开发脊髓球性肌萎缩症（SBMA）的有效治疗方法，SBMA是一种由雄激素受体（AR）中聚谷氨酰胺（polyQ）通道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，证明雄激素受体的天然功能是毒性的基本介质。具体来说，我们使用果蝇遗传学和功能基因组学的结合来了解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的重要步骤。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功能可能有效地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一发病机制，并进一步阐明受聚谷氨酰胺扩增干扰的特定AR功能，如所附提案所述。一个相关的问题是确定治疗中运动单元的最重要组成部分：运动神经元还是肌肉。为此目的，我们已开始进行试验，以实现三个具体目标。首先，我们培育了一系列新的转基因小鼠，这些小鼠有条件地表达野生型或突变型的人类雄激素受体，以在哺乳动物模型中证实这些发现。其次，我们将采用蛋白质组学方法来表征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，我们将在运动神经元或肌肉中设计条件表达，以评估这些组织对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. PUBLIC HEALTH RELEVANCE: Mutations in the androgen receptor gene cause an inherited neurodegenerative disorder called spinobulbar muscular atrophy. This project seeks to understand the molecular basis of this disease and provide detailed characterization of a promising therapeutic target. These insights will be used to guide therapeutic intervention for this disease and related degenerative diseases.