Spinal Muscular Atrophy-- SMNs role in motor neurons

描述(由申请人提供)： 脊髓性肌萎缩症是一种常染色体隐性遗传病，可引起 婴儿死亡率。SMA是由生存马达的缺失或突变引起的 神经元1基因(SMN1)和SMN2基因的保留。两个基因都是 无处不在的表达，但大部分来自SMN2基因的产物 缺少外显子7。这导致SMN2基因产生的SMN蛋白不足 运动神经元的正确功能。表型的严重性是 受SMN蛋白水平的调节，受SMN基因拷贝数的影响 SMN2基因。这项建议目的是确定哪些因素激活了SMN 表达，哪些组织、肌肉或神经需要高水平的SMN和 一个能够识别SMN关键功能的遗传系统 因为运动神经元是可以发育的。这将有助于解决这个问题：为什么 SMN缺乏会导致运动神经元紊乱吗？我们将决定什么是 通过识别转录激活SMN表达所需的 结合SMN启动子的因子。我们将确定哪些组织需要高 通过使小鼠在肌肉或运动中表达SMN来提高SMN的水平 并询问这些小鼠品系中的哪一个可以纠正SMA表型。 这项实验还将探讨运动神经元是否具有独特的敏感性。 达到SMN级别。非胆碱能神经元的SMN水平不会恢复。 如果SMN的剪接功能因蛋白质水平低而受损，这些 细胞应该退化。开发一种可用于 抑制器屏幕，能够识别关键的功能 运动神经元中的SMN，我们正在开发SMA的斑马鱼模型。斑马鱼 SMA模型还将允许对运动神经元发育的精确研究 SMA。这笔赠款将定义转录目标，这些转录目标可以用于 对SMA的治疗，这种组织需要高水平的SMN，并将提供 用于定义SMA缺乏的功能的遗传系统。这些发展将 在开发治疗SMA的方法方面发挥重要作用。

DESCRIPTION (provided by applicant): Spinal muscular Atrophy (SMA) is an autosomal recessive disease that can cause infant mortality. SMA is caused by the loss, or mutation, of the Survival Motor Neuron 1 gene (SMN1) and retention of the SMN2 gene. Both genes are ubiquitously expressed, but the majority of the product from the SMN2 gene lacks exon 7. This results in the SMN2 gene producing insufficient SMN protein for the correct function of motor neurons. The severity of the phenotype is modulated by SMN protein levels, which is influenced by the copy number of the SMN2 gene. The aim of this proposal is to determine what factors activate SMN expression, which tissue, muscle or nerve requires high levels of SMN and whether a genetic system capable of identifying the critical function of SMN for motor neurons can be developed. This will help address the question: Why does deficiency of SMN cause a motor neuron disorder? We will determine what is required for activation of SMN expression by identifying the transcription factors that bind the SMN promoter. We will determine what tissue requires high levels of SMN by making mice that express SMN in either muscle or motor neurons, and asking which of these mouse lines can correct the SMA phenotype. This experiment will also address whether motor neurons are uniquely sensitive to SMN levels. The SMN levels will not be restored in non-cholinergic neurons. If SMN's splicing function is impaired due to low levels of the protein, these cells should degenerate. To develop a genetic model system which can be used in suppressor screens, which are capable of identifying the critical function of SMN in motor neurons, we are developing a zebrafish model of SMA. The zebrafish SMA model will also allow precise studies on the motor neuron development in SMA. The grant will define the transcriptional targets, which could be used for treatment of SMA, the tissue that requires high levels of SMN and will give a genetic system to define the function lacking in SMA. These developments will be important in developing treatments for SMA.