组蛋白H3K27去甲基化修饰在新生神经元成熟与脑认知中的功能研究

学习记忆是大脑最基本也是最重要的高级神经功能之一。虽然海马神经发生被认为在调节学习和记忆过程中起着至关重要的作用，但其背后的分子调控机理，尤其表观遗传调控机制尚待深入揭示。近年来的研究发现，组蛋白修饰的异常往往与认知疾病密切相关。本课题将以组蛋白H3K27me3去甲基化修饰以及相关的去甲化酶UTX作为研究对象，分析它们在新生神经元成熟过程以及大脑认知中的功能；筛选鉴定其作用的下游靶基因；运用分子生物学与遗传学的手段干预关键信号分子的表达，评测其能否改善由去甲化酶基因缺失而导致的认知缺陷。本研究将为H3K27me3去甲基化修饰以及相关的去甲化酶在新生神经元成熟和大脑认知功能中的调控提供充实的理论和实验依据，为认知功能障碍疾病的治疗提供新的线索。

Learning and memory are the most important intellectual functions of the brain. It has been conclusively demonstrated that neurogenesis in the hippocampus is critical for learning and memory. However, the molecular and cellular mechanisms underlying neurogenesis, learning and memory have been remained elusive. Recent studies have shown a link between aberrant histone modification and cognitive diseases. This proposed project will focus on the functions of histone demethylase UTX (Ubiquitously Transcribed X Chromosome Tetratricopeptide Repeat Protein) in neurogenesis and cognition. We will characterize the deficits of neurogenesis, especially neuronal maturation, underlying the loss of UTX in the hippocampus. We will identify key downstream targets of UTX that play critical roles in regulating neuronal maturation, learning and memory. Finally, we will evaluate the therapeutic potentials of key downstream molecules of UTX in treating cognition deficits in UTX conditional knockout mice. This project will provide evidences for determining the roles of UTX in neuronal maturation, learning and memory, and clues to therapeutic strategies for treating learning and memory disorders.