RBBP4调控PKA-CREB-CBP信号通路参与癫痫相关记忆减退的作用及机制研究

海马在癫痫相关记忆减退病理过程中具有重要作用，前期基因芯片发现RBBP4是颞叶癫痫海马硬化伴记忆减退患者海马降低最为显著的基因。预实验显示RBBP4蛋白表达随着记忆障碍程度加重而降低，RBBP4可影响CREB的活性，PKA-CREB-CBP信号通路激活剂减少RBBP4转基因小鼠癫痫发作的棘波波幅和频率。据此我们提出假说：RBBP4调控PKA-CREB-CBP信号通路，进而损害癫痫患者记忆功能，RBBP4及其信号通路的激活将是防止乃至逆转癫痫相关记忆减退病程进展的新靶点。本课题拟从分子、细胞、组织以及动物水平明确RBBP4在癫痫相关记忆减退中的作用；探讨RBBP4及下游分子表达分布；确定RBBP4对PKA-CREB-CBP信号通路的调控；揭示RBBP4参与PKA-CREB-CBP信号通路导致癫痫相关记忆减退的机制。本研究将以RBBP4探讨癫痫记忆减退的发生机制，为癫痫记忆减退防治提供新思路。

Hippocampus plays an important role in the pathological process of epilepsy-related memory loss. Our previous study of Gene chip analyses found that RBBP4 is the most significant gene in hippocampus of patients with temporal lobe epilepsy and hippocampal sclerosis with memory loss. Previous results showed that the expression of RBBP4 protein decreases as the degree of memory impairment increases. RBBP4 can affect the activity of CREB. The PKA-CREB-CBP signaling pathway activator reduces the spike amplitude and frequency of seizures in RBBP4 transgenic mice. Based on this, we hypothesized that RBBP4 can impair the memory function of patients with epilepsy by regulating the PKA-CREB-CBP signaling pathway. Activation of RBBP4 and its signaling pathways will be a new target for preventing or even reversing the progression of epileptic-related memory loss. This study intends to clarify the role of RBBP4 in epilepsy-related memory loss from molecular, cellular, tissue and animal levels; to explore the expression and distribution of RBBP4 and its downstream molecules in human epilepsy samples and animal models of epilepsy; to determine the regulation of RBBP4 on PKA-CREB-CBP signaling pathway; to reveal the mechanism of RBBP4 leading to epileptic-related memory loss through PKA-CREB-CBP signaling pathway. This study will use RBBP4 as a new point of view to explore the mechanism of memory loss in epilepsy, and provide new ideas for prevention and treatment of memory loss in epilepsy.