The Neural Functions of Rai1, the Causal Gene for Smith-Magenis Syndrome

项目总结/摘要 这项提案的长期目标是建立成功的独立实验室，使用小鼠模型， 研究神经生物学和Smith-Magenis综合征（SMS）的治疗，这是一种破坏性的神经发育障碍。 由RAI1的单倍不足引起的疾病。SMS患者表现出突出的神经系统症状，包括 智力障碍、睡眠障碍、癫痫发作、张力减退、自伤行为和自闭症特征。 我们最近发现Rai1是一个转录因子，它促进了几个基因的表达 对神经元形态发生和神经传递很重要。然而，Rai1 调节神经元的形态和活动，从而引起神经行为症状尚不清楚。 此外，我们还缺乏对开发期间何时需要RAI1的基本理解， 神经功能，以及如果RAI1剂量在成人中恢复，SMS症状是否可逆。的 该建议的目标是（1）确定Rai 1要求的临界时间窗口，并校正 SMS样表型;（2）确定Rai1在神经元形态发生中的作用;（3）确定 Rai1塑造神经元活动。中心假设是Rai 1调节形态发生和回路 活性稳态在关键时间窗口中恢复Rai1将改善至少一些SMS类 小鼠的表型。这一假设将结合使用尖端的神经科学技术进行测试 用新的老鼠遗传工具。完成拟议的实验将确定的可逆性 SMS的各种神经行为和生理表型，识别关键治疗窗口，以及 阐明SMS症状的解剖学和活动水平缺陷。这些结果将作为 未来研究的基础旨在扭转这些赤字。 该奖项的指导阶段将由一个世界知名的神经科学家团队监督，包括Dr。 Liqun Luo，John Huguenard，Mehrdad Shamloo，and John Swann.完成辅导阶段后 该项目专注于研究Rai1在神经元形态和活动中的作用，PI将能够将 Rai1的分子功能与其行为功能的关系。提出了一项全面的培训计划， 在单细胞树突形态学分析和电生理记录方面的额外教育。 完成本提案将提供必要的技能，过渡到一个独立的教师职位， 顶级研究机构。

PROJECT SUMMARY/ABSTRACT The long-term goal of this proposal is to establish successful independent laboratory using mouse models to study the neurobiology and treatment of Smith-Magenis Syndrome (SMS), a devastating neurodevelopmental disorder caused by haploinsufficiency of RAI1. SMS patients exhibit prominent neurologic symptoms, including intellectual disabilities, sleep disturbances, seizures, hypotonia, self-injurious behaviors, and autistic features. We recently discovered that Rai1 is a transcription factor that promotes the expression of several genes important for neuronal morphogenesis and neurotransmission. However, the mechanism by which Rai1 regulates neuronal morphology and activity, thereby causing the neurobehavioral symptoms is unclear. Furthermore, we also lack fundamental understanding about when during development is RAI1 required for neural functions, and whether SMS symptoms are reversible if RAI1 dosage is restored in adults. The objectives of this proposal are to (1) determine critical temporal windows for Rai1 requirement and correct SMS-like phenotypes; (2) determine the role of Rai1 in neuronal morphogenesis; and (3) determine how loss of Rai1 shapes neuronal activity. The central hypothesis is that Rai1 regulates the morphogenesis and circuit activity homeostasis. Restoring Rai1 in critical temporal windows will ameliorate at least some SMS-like phenotypes in mice. This hypothesis will be tested using cutting-edge neuroscience techniques in combination with novel mouse genetic tools. Completion of the proposed experiments will determine the reversibility of various neurobehavioral and physiological phenotypes of SMS, identify the critical treatment window, and elucidate the anatomical and activity level deficits underlying SMS symptoms. These results will serve as the foundation for future studies aimed to reverse these deficits. The mentored phase of this award will be overseen by a team of world renowned neuroscientists including Drs. Liqun Luo, John Huguenard, Mehrdad Shamloo, and John Swann. Upon completion of the mentored phase that focuses on studying the role of Rai1 in neuronal morphology and activity, the PI will be able to link the molecular functions of Rai1 to its behavioral functions. A comprehensive training plan was proposed to include additional education in single cell dendritic morphological analysis and electrophysiological recordings. Completion of this proposal will provide the necessary skills to transition to an independent faculty position at a top research institution.