脊髓性肌肉萎缩症（SMA）是儿童常见致死性遗传病，因缺乏SMN导致脊髓α运动神经元变性，继而引起骨骼肌萎缩，患者呼吸衰竭而亡。至今缺乏SMN引发SMA的分子机制仍不明了、也无治疗药物。传统观点认为提高脊髓运动神经元SMN水平是治疗SMA的必要条件。近期我们在《Nature》和《Genes & Development》报道，提高小鼠模型外周组织SMN水平能极大延长小鼠寿命，改善运动能力，表明外周SMN水平提高不仅维护外周组织功能也保护运动神经元。我们提出假设：SMA小鼠外周组织存在严重缺陷，是导致小鼠过早死和运动神经元变性的根本原因。本项目我们将对小鼠模型各组织进行全面系统的病理分析，找出关键病变组织，利用转录组和蛋白组分析寻找SMN下游的关键基因，探索异常表达基因和相关组织在疾病发展中的作用和治疗价值。本项目将不仅阐明SMA分子病理机制也为药物开发打下基础，因此具有重要理论意义和应用价值。

Spinal muscular atrophy (SMA) is the most common genetic disease in young children, caused by lack of survival of motor neuron (SMN) protein. SMA is characterized by degeneration of spinal-cord α-motor neurons, which leads to progressive atrophy of voluntary muscles, and finally patients die from respiratory failure. So far, the molecular mechanisms of SMA pathogenesis remain elusive, and there is no effective treatment. It has been generally accepted that spinal cord motor neurons are the principal and directly affected cells in SMA; therefore, increasing SMN in the CNS, particularly the spinal cord motor neurons is at least required, if not sufficient, for SMA therapy. Surprisingly, we recently observed an efficient motor-neuron cell-nonautonomous rescue of severe SMA mice including a robust survival increase and great improvement of motor function, demonstrating that increase of SMN in peripheral tissues not only restores normal functions of peripheral cells and tissues but also preserves motor neurons and neuromuscular junctions. This raised a question: which peripheral tissues or organs are critical in premature death and motor neuron degeneration of SMA mice? We hypothesize that critical defects are present in peripheral tissues of SMA mice and the defects not only cause the premature death but also motor neuron degeneration by failing to supply essential neurotrophic factors or prevent the production of toxic factors that affect motor neuron maintenance. In this project we will systematically analyze histopathology, transcriptome and proteome of various tissues and organs of a severe SMA mouse model, explore the critical pathways downstream of SMN, and evaluate the importance of certain disrupted signaling pathways and potentially defective tissues in rescuing SMA mice.