Pathways of Neurodegeneration in SBMA

描述(申请人提供)：拟议研究的长期目标是开发有效的治疗脊髓延髓肌萎缩症(SBMA)，这是一种由雄激素受体(AR)中的聚谷氨酰胺(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，证明雄激素受体的天然功能是毒性的基本媒介。具体地说，我们结合了果蝇遗传学和功能基因组学来了解AR的AF-2结构域与核激素共调节蛋白的相互作用是发病过程中的一个重要步骤。这一令人兴奋的发现表明，用现有的抗雄激素疗法调节自然AR功能可能对治疗这种毁灭性的神经退行性疾病有效。关键的下一步是在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张干扰的特定AR功能，如所附提案中所概述的。一个相关的问题是确定治疗中要针对的运动单位最重要的组成部分：运动神经元还是肌肉。为此，我们启动了实验，以解决三个具体目标。首先，我们已经产生了一系列有条件地表达野生型或突变型人雄激素受体的转基因小鼠，以在哺乳动物模型中证实这些发现。其次，我们将寻求蛋白质组学方法来表征多谷氨酰胺扩张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小鼠退化表型的相对贡献。 与公共卫生相关：雄激素受体基因突变导致一种遗传性神经退行性疾病，称为脊髓延髓肌肉萎缩症。这个项目试图了解这种疾病的分子基础，并提供一个有希望的治疗靶点的详细特征。这些见解将用于指导对本病和相关退行性疾病的治疗干预。

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.