Targeting disease pathways in models of Spinal and Bulbar Muscular Atrophy

脊髓和球性肌肉萎缩症（SBMA），也被称为肯尼迪氏病，是一种成人发病缓慢进展的退行性神经肌肉疾病，主要影响男性。它是由编码雄激素受体（AR）基因内CAG扩增的聚谷氨酰胺引起的。AR介导雄激素如睾酮的作用，并作为配体依赖性转录因子发挥作用。然而，肌肉萎缩和运动神经元退化的分子基础尚不清楚。因此，本项目的目的是了解SBMA的两个主要病理部位（脊髓运动神经元和骨骼肌）的潜在疾病机制，以便针对这些部位进行治疗。本研究将使用具有良好特征的SBMA小鼠模型以及患者源性干细胞（iPSC）。特别是，我们将对我们最近从SBMA小鼠脊髓和后肢肌肉中激光捕获的运动神经元的RNA-seq数据进行分析，以及SBMA患者肌肉活检的基因表达数据，以建立疾病途径。接下来将对SBMA患者的人类干细胞（h-iPSC）衍生的运动神经元进行rna测序。在SBMA小鼠、患者iPSCs和患者肌肉活检中，基因和通路失调的功能后果将在体外使用原代小鼠运动神经元和肌肉培养以及患者iPSCs进行研究，以确定靶向这些通路是否可能是SBMA的可行治疗方法。我们希望对SBMA发病机制的基因和途径的鉴定将导致在SBMA小鼠的临床前试验中对药物靶点进行体内测试，以确定它们是否对疾病进展有任何可观察到的影响。此外，通过在体内和体外以及在两种不同的SBMA模型（一种小鼠和另一种人源性干细胞）中测试潜在的治疗方法，将大大增强对可行治疗靶点的识别。

Spinal and Bulbar Muscular Atrophy (SBMA), also known as Kennedy's disease, is an adult-onset slowly progressing degenerative neuromuscular disorder which predominantly affects males. It is caused by a polyglutamine encoding CAG expansion within the androgen receptor (AR) gene. The AR mediates the effect of androgens such as testosterone and functions as a ligand-dependent transcription factor. However, the molecular basis of muscle atrophy and motor neuron degeneration is as yet unknown. Therefore, the aim of this project is to understand the underlying disease mechanisms in the two primary sites of pathology in SBMA, spinal cord motor neurons and skeletal muscle, allowing for therapeutic targeting of these sites. A well characterised mouse model of SBMA, as well as patient derived stem cell (iPSC) will be used in this study. In particular, analysis will be undertaken on our recent RNA-seq data from laser captured motor neurons from spinal cord and hindlimb muscle of SBMA mice, as well as gene expression data from SBMA patient muscle biopsies to establish the disease pathways. This will be followed up by performing RNA-seq from human stem-cell (h-iPSC) derived motor neurons from SBMA patients. The functional consequences of the genes and pathways dysregulated in SBMA mice, patient iPSCs and patient muscle biopsies will be studied in vitro using primary mouse motor neuron and muscle cultures, as well as patient iPSCs, to establish if targeting these pathways may be a viable therapeutic approach for SBMA. We hope that identification of the genes and pathways that underlie SBMA pathogenesis will lead to in vivo testing of drug targets in a pre-clinical trial in SBMA mice to establish if they have any observable effect on disease progression. Furthermore, by testing potential therapies both in vivo and in vitro, as well in two different models of SBMA, one mouse and the other human derived stem cells, identification of viable therapeutic targets will be greatly enhanced.