Identifying the insulin-signaling targets that regulate synapse development

识别调节突触发育的胰岛素信号传导靶点

• 批准号: RGPIN-2017-06738
• 负责人: Zhen, Mei
• 金额: $ 3.64万
• 依托单位: University of Toronto
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=712358
• 关键词: Identifying; insulin; signaling; targets; regulate

Our nervous system needs to generate and maintain functional neuronal and neuron-muscle connections. Using C. elegans, a small animal model, we discovered that an attenuation of insulin signalling not only restores the morphology and function of the neuron-muscle connection (called neuromuscular junctions) in genetic mutants with defective neuromuscular junction developments, but also exerts strong protection in animal models for neurodegeneration. Intriguingly, both the developmental and neural protective role of insulin signalling involves secretion of insulin from the nervous system, and the activation of a signalling cascade in the muscle cells, and both roles strictly depend on the presence of a transcription factor called DAF-16 in muscles. Hence, identification of muscle-specific DAF-16 transcriptional targets becomes critical for an understanding and biomedical application of the developmental and protective roles of insulin signalling. The goal of our project is to identify the DAF-16 transcriptional targets. Specifically, we will first utilize the C. elegans model to identify genes whose expression is specifically activated or repressed by DAF-16 in muscle cells, and perform functional assay to identify those that are critical for animals to maintain robust neuromuscular junction morphology and function. Upon the identification of such targets, we will further examine their biomedical impact by examining whether they affect the neuromuscular junction phenotype and function in the C. elegans neurodegenerative models, and whether they have functional conservation using a human iPS cell-derived in vitro neuromuscular system.

我们的神经系统需要产生和维持功能性的神经元和神经元与肌肉的联系。利用秀丽隐杆线虫（一种小型动物模型），我们发现胰岛素信号的衰减不仅可以恢复神经肌肉连接发育缺陷的基因突变体的神经肌肉连接（称为神经肌肉连接）的形态和功能，而且还可以在神经变性动物模型中发挥强大的保护作用。有趣的是，胰岛素信号的发育和神经保护作用都涉及神经系统的胰岛素分泌和肌肉细胞信号级联的激活，这两种作用都严格依赖于肌肉中称为DAF-16的转录因子的存在。因此，识别肌肉特异性DAF-16转录靶点对于理解和生物医学应用胰岛素信号传导的发育和保护作用至关重要。