DE PEDIATRIC COBRE: MECHANISMS OF CELL DEATH IN SPINAL MUSCULAR ATROPHY

脊髓性肌萎缩症（SMA）是一种以运动神经元变性和进行性肌肉萎缩为特征的神经肌肉疾病。这种疾病是婴儿死亡最常见的遗传原因之一。负责SMA的基因，存活运动神经元（SMN），在人类中以两个几乎相同的拷贝（SMN1和SMN2）存在。只有基因（SMN1）的端粒拷贝的缺失或突变才会导致疾病。已知SMN蛋白在RNA剪接复合体的组装中起作用，然而，SMN缺乏导致SMA细胞死亡的机制尚不清楚。我们的长期目标是了解SMA中运动神经元死亡的机制，并开发一种预防方法。SMN

Spinal muscular atrophy (SMA) is a neuromuscular disease characterized by degeneration of motor neurons and progressive muscle atrophy. The disease is one of the most common genetic causes of infant death. The gene responsible for SMA, survival motor neuron (SMN), exists in humans as two nearly identical copies (SMN1 and SMN2). Only deletion or mutation(s) of the telomeric copy of the gene (SMN1) causes the disease. The SMN protein has been known to function in assembly of the RNA splicing complex, however, Ithe mechanism(s) by which SMN-deficiency causes cell death in SMA are not clear. Our long-term goal is to lunderstand the mechanism(s) of motor neuron death in SMA and develop a means of prevention. SMN Iprotein has been reported to have some survival promoting functions in cultured cells. Our preliminary studies show that skin fibroblasts from SMA patients are more sensitive to certain death promoting stimuli than control fibroblasts. We hypothesize that the SMN protein is directly involved in cell survival and that toss of SMN's survival function results in motor neuron death in SMA. We will use fibroblasts from SMA patients, PC12 cells, and rat primary motor neuron cultures as model systems to test our hypothesis. We will determine the effect of expression of SMN protein in regulating cell death of SMA fibroblasts. We will further investigate the role of SMN in neuronal cell survival. Finally, we will determine biological pathway(s) of SMNmediated cell protection. Results from the proposed studies will provide insight into the mechanism(s) and signaling pathway(s) by which SMN protects cells from death and how a decrease in SMN function leads to the SMA phenotype. Ultimately, the obtained information could lead to develop therapeutic strategies to intervene.