Generation and characterization of a zebrafish model of SBMA

脊髓延髓肌萎缩症（SBMA）是一种缓慢进行的X连锁神经肌肉疾病， 这是无法治愈的在成年男性中出现，其表型特征为近端肢， 延髓肌无力、肌束震颤和肌肉萎缩，由下丘脑功能障碍和变性引起。 运动神经元和骨骼肌。该项目的目的是产生一个更具成本效益，高- 通量和疾病相关的SBMA体内模型系统。支持斑马鱼作为 SBMA的疾病相关模型包括人类和斑马鱼神经解剖学的高度结构同源性 和肌肉生理学。此外，斑马鱼不像它们的小型研究动物苍蝇和蠕虫， 表达雄激素受体（AR），这种AR在结构和功能上与人类AR相似，表明 斑马鱼，除了它是脊椎动物这一事实外，将作为一个上级高通量模型 关于SBMA由于SBMA中的致病突变是AR蛋白中的多聚谷氨酰胺扩增，我们的目标是 产生表达多聚谷氨酰胺扩增的AR的斑马鱼转基因系，以及对照， 正常谷氨酰胺长度AR。我们假设表达多聚谷氨酰胺扩增的AR的雄性斑马鱼将 表现出与小鼠模型和SBMA中观察到的相似的运动功能缺陷和组织病理学 患者SBMA的斑马鱼模型将提供一个强大的，廉价的脊椎动物模型，以补充 目前的动物模型，并加快该患者群体的治疗开发。

Spinal and bulbar muscular atrophy (SBMA) is a slowly progressive X-linked neuromuscular disease, for which there is no cure or therapy. Arising in adult males, it is phenotypically characterized by proximal limb and bulbar muscle weakness, fasciculations, and muscle atrophy, caused by dysfunction and degeneration of lower motor neurons and skeletal muscle. The purpose of this project is to generate a more cost-effective, high- throughput, and disease relevant in vivo model system of SBMA, using zebrafish. Support for zebrafish as a disease relevant model of SBMA includes the high structural homology of human and zebrafish neuroanatomy and muscle physiology. Moreover, zebrafish, unlike their small research animal counterparts, flies and worms, express an androgen receptor (AR), and this AR is similar in structure and function to human AR, indicating that the zebrafish, in addition to the fact that it is a vertebrate, would serve as a superior high-throughput model of SBMA. As the disease causing mutation in SBMA is a polyglutamine expansion in the AR protein, we aim to generate a transgenic lines of zebrafish that express polyglutamine-expanded AR, as well as the control, normal glutamine length AR. We postulate that male zebrafish expressing polyglutamine-expanded AR will manifest motor function deficits and histopathology similar to those observed in mouse models and SBMA patients. A zebrafish model of SBMA would provide a powerful, inexpensive, vertebrate model to complement current animal models and expedite therapeutic development for this patient population.