Identification of human-relevant CLOCK molecular signaling pathways

 描述(由申请人提供)：自闭症谱系障碍患者睡眠和昼夜节律紊乱显著并存的潜在分子机制尚不清楚。越来越多的证据表明，自闭症的核心昼夜节律因子发生了基因和基因组的改变。转录因子时钟在视交叉上核内的昼夜节律功能中的作用已经被充分研究，但它在大脑的其他部分的作用是 不太为人所知。我们观察到，与其他灵长类动物相比，人类大脑皮层的时钟表达显著增加，时钟共表达发生了变化。因此，我们假设，时钟介导的转录网络特定于人类新皮质，参与昼夜节律和认知功能，并在诸如ASD等认知障碍中受到干扰。为了验证这一假说，我们建议识别特定于人类神经元的受时钟调控的转录网络。我们将使用三个系统来确定人类时钟的转录靶点：原始人类神经前体细胞及其分化的神经元、人死后新皮质组织和表达人类时钟及其调控元件的小鼠。这种利用进化数据为认知疾病指导的功能研究提供信息的新方法，应该为人类大脑进化的一些方面提供重要的新见解，这些方面在具有昼夜节律成分的认知障碍中风险最大。

 DESCRIPTION (provided by applicant): The molecular mechanisms underlying the significant co-morbidity of sleep and circadian disturbances in patients with autism spectrum disorder remain unknown. There is mounting evidence for genetic and genomic alteration to core circadian factors in autism. The transcription factor CLOCK has been well-studied for its role in circadian function within the suprachiasmatic nucleus, but its role in other parts of the brain are not well known. We have observed that the human neocortex has a significant increase in CLOCK expression and altered CLOCK coexpression compared to other primates. We therefore hypothesize that CLOCK-mediated transcriptional networks specific to the human neocortex are involved in circadian and cognitive function and are disrupted in cognitive disorders such as ASD. To test this hypothesis, we propose to identify the transcriptional networks regulated by CLOCK specifically in human neurons. We will determine transcriptional targets of human CLOCK using three systems: primary human neural progenitors and their differentiated neurons, human neocortical post-mortem tissue, and mice expressing human CLOCK together with its regulatory elements. This novel approach of using evolutionary data to inform cognitive disease directed functional studies should provide important new insights into aspects of human brain evolution that are most at risk in cognitive disorders with a circadian component.