Mammalian motor neuron SMN screens

脊髓性肌萎缩症（SMA）是一种常见的儿童常染色体隐性遗传病， 运动神经元存活基因SMN1（Survival of Motor Neuron 1）SMA的主要特征之一是 进行性神经肌肉功能丧失，往往是致命的，使SMA的主要遗传原因， 婴儿和幼儿死亡。运动神经元死亡是这种疾病的一个显著特征，但一些 最近的信息表明，肌肉功能障碍或畸形也可能发生。虽然SMN 似乎具有多重细胞作用，目前尚不清楚其中哪些支持神经肌肉 发展和健康，合理数量的患者信息表明，较高水平的SMN 表达与不太严重的疾病病例相关。这表明了一个明确的治疗策略： 即，确定增加SMN水平的途径和最终的药物类别。但 是替代策略，其中之一是寻找独立于SMN发挥作用的途径， 当SMN水平降低时进行校正。为了实现这一目标，我们和我们的合作者进行了 两个屏幕。第一组使用化学和生物库来搜索化合物， 增加小鼠运动神经元和其他细胞中SMN的量。第二组使用基因 寻找能够改善蝇和蠕虫模型中SMA表型的基因的方法。我们将建立一个 一套关键的表型分析来测试筛选出来的所有化合物和基因。 这些将包括小鼠运动神经元存活，骨骼肌发育和神经肌肉发育。 结的形成此外，我们将在人类运动神经元上测试这些化合物和基因 由SMA患者的诱导多能干细胞（iPS）产生。确定的目标 化学筛选将在遗传模型中进行交叉验证。因此，所有屏幕的点击率将 严格评估和比较。最后，从这些筛选中鉴定的化合物将在 小鼠SMA模型。这项工作的最终结果应该是彻底表征的化合物， 可以潜在地用于开发治疗这种儿童疾病的药物。

Spinal muscular atrophy (SMA) is a common childhood autosomal recessive disease caused by mutafions in the Survival of Motor Neuron 1 (SMN1) gene. One of the primary features of SMA is the progressive loss of neuromuscular function that is often fatal, making SMA the leading genetic cause of death in infants and young children. Motor neuron death is a significant feature of this disease, but some recent informafion suggests that muscle dysfuncfion or malformafion may also occur. While SMN appears to have mulfiple cellular roles, and it is not yet clear which of them support neuromuscular development and health, a reasonable amount of patient informafion indicates that higher levels of SMN expression are associated with less severe cases of disease. This suggests a clear therapeutic strategy: namely, identifying the pathways and, ultimately, drug classes that increase SMN levels. However, there are alternate strategies, one of which is finding pathways that function independently of SMN and are corrective when SMN levels are reduced. To accomplish this, we and our collaborators have carried out two sets of screens. The first set used chemical and biological libraries to search for compounds that increase amounts of SMN in mouse motor neurons and other cells. The second set used genetic methods to find genes that can ameliorate SMA phenotypes in fiy and worm models. We will establish a set of key phenotypic assays to test all of the compounds and genes that come out of the screens. These will include mouse motor neuron survival, skeletal muscle development and neuromuscular junction formafion. In addition, we will test these compounds and genes on human motor neurons produced from induced pluripotent stem (iPS) cells made from an SMA patient. Targets identified from chemical screens will be cross-validated in genetic models. Thus, hits from all the screens will be evaluated and compared rigorously. Finally, compounds indentified from these screens will be tested in mouse SMA models. The end result of this work should be thoroughly characterized compounds that can potenfially be used to develop therapeufics for this childhood disease.