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，由 运动神经元1(SMN1)基因生存中的突变SMA的主要功能之一是 进行性神经肌肉功能丧失，通常是致命的，使SMA成为导致 婴幼儿死亡。运动神经元死亡是这种疾病的一个重要特征，但有些 最近的信息表明，肌肉功能障碍或畸形也可能发生。而SMN 似乎具有多重细胞作用，目前尚不清楚它们中哪些支持神经肌肉 发展和健康，合理的患者信息表明SMN水平较高 这种表达与不太严重的疾病病例有关。这表明了一个明确的治疗策略： 也就是说，确定提高SMN水平的途径，并最终确定药物类别。然而，在那里 是替代策略，其中之一是寻找独立于SMN运行的路径，并且 当SMN水平降低时进行纠正。为了实现这一目标，我们和我们的合作者进行了 两套屏幕。第一组使用化学和生物文库来搜索能够 增加小鼠运动神经元和其他细胞中SMN的数量。第二组使用的是基因 方法在飞行和蠕虫模型中寻找可改善SMA表型的基因。我们将建立一个 一套关键的表型分析来测试所有来自筛查的化合物和基因。 这些将包括小鼠运动神经元存活、骨骼肌发育和神经肌肉 结合处形成黑手党。此外，我们还将在人类运动神经元上测试这些化合物和基因 从SMA患者的诱导多能干细胞(IPS)中产生。确定的目标来自 化学筛选将在遗传模型中进行交叉验证。因此，所有屏幕的点击量都将是 严格评估和比较。最后，从这些筛查中鉴定出的化合物将在 鼠标SMA型号。这项工作的最终结果应该是彻底表征化合物 可能被用来开发这种儿童疾病的治疗方法。

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.