Molecular and Cellular Basis of Neurodevelopmental Disorders

项目摘要/摘要 神经发育障碍是一种常见的、使人衰弱的疾病，包括自闭症、智力残疾和 甚至可能是精神分裂症。最近的遗传学研究发现，在不同的基因中存在多个基因突变 细胞通路是包括自闭症谱系障碍在内的神经发育障碍的遗传原因， 智力残疾，以及其他。这项提议将表征新的和创新的遗传小鼠模型 来描述这些基因在大脑中的功能。具体地说，该提案将重点关注两个基因 与16p11.2缺失或自闭症有关，这两种情况都被预测与重叠的Intra- 神经信号通路与神经元和突触功能/发育的调节 初步调查结果。除了确定这些基因在大脑中的神经功能外，这些研究 将确定治疗遗传性自闭症和智力残疾的潜在治疗策略 可能还有其他神经发育障碍。迄今为止，在两个新突变体方面取得了实质性进展 与神经发育障碍相关的小鼠模型已经建立并初步 突触功能、神经元发育、神经元生化和神经元形态的特征 在大脑功能的其他方面已经开始。无偏见的蛋白质组学/转录组学鉴定方法 另外，哺乳动物大脑中这些基因产物的新下游靶点将产生新的 假说预计会导致更多潜在的治疗策略。

Project Summary/Abstract Neurodevelopmental disorders are common, debilitating disorders including autism, intellectual disability, and perhaps even schizophrenia. Recent genetic findings have identified mutations in multiple genes in various cellular pathways as genetic causes of neurodevelopmental disorders including autism spectrum disorders, intellectual disability, and others. This proposal will characterize novel and innovative genetic mouse models to delineate the function of these genes in the brain. Specifically, the proposal will focus on two genes implicated in either 16p11.2 deletion or autism, both of which are predicted to be involved in overlapping intra- neuronal signaling pathways and regulation of neuronal and synaptic function/development based on preliminary findings. In addition to identifying the neuronal function of these genes in the brain, these studies will identify potential therapeutic strategies for treatment of genetic forms of autism and intellectual disability and possibly other neurodevelopmental disorders. Progress to date is substantial in that two novel mutant mouse models relevant for neurodevelopmental disorders have been established and preliminary characterization of synaptic function, neuronal development, neuronal biochemistry, and neuronal morphology among other aspects of brain function has begun. Unbiased proteomic/transcriptomic approaches to identifying additional, novel downstream targets of these gene products in mammalian brain will generate new hypotheses anticipated to lead to additional potential therapeutic strategies.