Study of AR transcriptional network in stem cell model of SBMA

X连锁脊髓延髓肌萎缩症（也称为SBMA或肯尼迪病）是一种 一种罕见的神经肌肉疾病，以成人发作的近端肌无力为特征， 下运动神经元变性SBMA患者表现出雄激素不敏感的迹象， 包括男性乳房发育、生育能力降低和睾丸萎缩。SBMA是由CAG引起的- 雄激素受体（AR）基因中的多聚谷氨酰胺（polyQ）重复扩增，是 包括亨廷顿氏病在内的九种CAG-polyQ重复序列疾病的家族。为 几十年来，对神经系统疾病基础的研究集中在以下方面的贡献： 神经元功能障碍与疾病发病机制的关系。然而，在过去的十年里， 运动神经元疾病领域越来越多的证据挑战了流行的神经中心主义 许多神经系统疾病的病因学理论。.在SBMA的情况下， 证据表明肌肉功能障碍是疾病发病机制的主要组成部分。为 然而，不同的研究小组已经证明了成功的治疗方法， 使用不同的SBMA动物靶向骨骼肌或中枢神经系统 模型因此，在文献中缺乏共识强调了研究的必要性 SBMA AR突变对受影响的细胞类型-骨骼肌和运动神经元-在一个 人类背景我们假设polyQ突变会导致AR与 导致运动神经元中致病的转录失调的DNA， 骨骼肌或两者。因此，该提议的目标是将联合收割机AR全基因组 从SBMA和CRISPR工程化产生的占据和基因表达数据集 同基因控制iPSC衍生的骨骼肌和运动神经元。我们将共同培养 具有iPSC衍生的运动神经元的iPSC衍生的骨骼肌调节AR靶 在AR转录网络中鉴定，并通过以下方法研究神经肌肉接头（NMJ）： 分析运动神经元和骨骼肌的电生理活动。这项工作 将进一步了解人类突变AR对SBMA的分子机制 发病机制和评估iPSC衍生的骨骼肌和运动神经元工具的效用 开展SBMA体外研究。

X-linked spinal and bulbar muscular atrophy (also known as SBMA or Kennedy's disease) is a rare neuromuscular disorder characterized by adult-onset proximal muscle weakness due to lower motor neuron degeneration. SBMA patients display signs of androgen insensitivity, including gynecomastia, reduced fertility, and testicular atrophy. SBMA, is caused by a CAG- polyglutamine (polyQ) repeat expansion in the androgen receptor (AR) gene and is one member of a family of nine CAG-polyQ repeat disorders that includes Huntington’s disease. For decades, research into the basis of neurological disease focused upon the contribution of neuronal dysfunction to disease pathogenesis. However, over the last ten years, there has been growing evidence in the motor neuron disease field that challenges the prevailing neurocentric theory of the etiology of many neurological diseases. . In the case of SBMA, there is increasing evidence implicating muscle dysfunction as a major component of disease pathogenesis. For therapeutic purposes, however, different groups have demonstrated successful treatments targeting either the skeletal muscles or the central nervous system using different SBMA animal models. Consequently, this lack of consensus in the literature underscores the need for studies of the SBMA AR-mutation on affected cell types - skeletal muscles and motor neurons - in a human background. We hypothesized that polyQ mutation cause disruption in AR binding to the DNA which leads to transcriptional dysregulation that can be pathogenic in motor neurons, skeletal muscles or both. Therefore, the goal of this proposal is to combine AR genome wide occupancy and gene expression data sets generated from SBMA and CRISPR engineered isogenic controls iPSC-derived skeletal muscle and motor neurons. We will then, co-culture the iPSC-derived skeletal muscles with iPSC-derived motor neurons to modulate the AR targets identified in the AR transcriptional network and investigate neuromuscular junctions (NMJ) by analyzing electrophysiological activity of the motor neurons and the skeletal muscles. This work will advance understanding on the molecular mechanisms of human mutant AR to SBMA pathogenesis and evaluate the utility of iPSC-derived skeletal muscles and motor neurons tool to develop SBMA in vitro studies.