Reference number : GC-2017-Q1-03463, amendment number : , agreement type : G, recipient legal name : Zhen, Mei (University of Toronto), recipient country : CA, recipient province : nan, recipient city : Ontario, recipient postal code : nan, program name english : Discovery Grants Program - Individual, program name french : Programme de subventions à la découverte - individuelles, program purpose english : 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., program purpose french : 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., agreement title english : Identifying the insulin-signaling targets that regulate synapse development, agreement title french : Identifying the insulin-signaling targets that regulate synapse development, agreement number : RGPIN, agreement value : 250000.0, agreement start date : 2017-05-10, agreement end date : nan, description english : nan, description french : nan, expected results english : nan, expected results french : nan, additional information english : Grant or Award spanning more than one fiscal year. (2017-2018 to 2022-2023), additional information french : Subvention ou bourse octroyée s'appliquant à plus d'un exercice financier. (2017-2018 à 2022-2023), owner organization : nserc-crsng, owner organization title : Natural Sciences and Engineering Research Council of Canada | Conseil de recherches en sciences naturelles et en génie du Canada