BOD1影响突触功能诱发智力障碍的分子机制及调控研究

Intellectual disability (ID) is a severe neurological disorder characterized with cognitive dysfunction and psychological disability due to incomplete brain development. The Social medical system faces heavy burden, but the exact pathological mechanism of ID is still unknown. While clinical genome-wide linkage analysis and mutation screening of ID patients revealed that there is a nonsense mutation in BOD1 (Biorientation of chromosomes in cell division 1) gene, this rise interesting question that aberrant BOD1 expression might participate in the pathological process of ID. Our recent study revealed that BOD1 protein was highly expressed in dendrites of pyramidal neurons. Moreover, the learning and memory function of Bod1 knockout mice was significantly impaired in contrast to that of wild-type mice. We will carry out the following studies to examine the role of BOD1 in the present project: 1) To elucidate the effect of BOD1 on hippocampal synaptic plasticity, neural circuits and behaviors in mice; 2) To explore the mechanism and signaling pathways of BOD1 in regulation of the function of synapses and neural circuits by genomics and molecular biology techniques. 3) To further address the correlation between BOD1 and ID by intervening BOD1 downstream target molecules via pharmacological and gene manipulations. The study not only reveal the pathological mechanism of ID but also provide new drug targets for the prevention and treatment of mental retardation.

智力障碍是由于大脑发育不完全或损伤引起患者认知及心理活动的障碍，社会医疗负担沉重，但智力障碍的发病机制至今不明。前期研究通过对智力障碍的全基因组连锁分析与突变筛选发现BOD1基因存在无义突变，提示BOD1基因与智力障碍密切相关。我们前期研究发现BOD1在锥体神经元树突高丰度表达; 我们构建的Bod1基因敲除小鼠其学习记忆能力明显低于野生型小鼠。因此，本项目将继续开展以下相关研究：1）阐明BOD1功能缺失对海马区神经元突触可塑性、神经环路及小鼠认知功能障碍关联行为学的影响；2）通过基因组学和分子生物学技术，探讨BOD1分子通过何种信号通路影响突触和神经环路的功能；3）采用药理学和基因调控手段对BOD1上下游靶点分子进行干预，发现智力障碍治疗潜在药物靶标。本课题开展将进一步揭示智力障碍的发病机制，为智力障碍的预防和治疗提供新的研究思路和治疗策略。

背景：智力障碍是由于大脑发育不完全或损伤引起认知及心理活动的障碍，但智力障碍的发病机制至今不明。临床通过对智力障碍的全基因组连锁分析与突变筛选发现BOD1基因存在无义突变，揭示BOD1基因与智力障碍密切相关, 但BOD1基因突变导致智力障碍的机制未被阐明。.主要研究内容：1）阐明BOD1对海马区神经元突触可塑性、神经环路及小鼠行为的影响；2）通过基因组学和分子生物学技术，探讨BOD1蛋白通过何种信号通路影响突触和神经环路的功能；3）采用药理学和基因调控手段对BOD1下游靶点分子进行干预，更深层次揭示BOD1与智力障碍的相关性。.重要结果及关键数据：1）构建的CaMKII-Cre; Bod1f/f基因敲除小鼠的学习记忆能力明显低于野生型小鼠；2）对Bod1敲除小鼠海马脑区的锥体神经元电生理记录研究，通过对神经元不同受体的刺激并诱导确认Bod1对AMPD受体没有影响，但其改变了NMDA受体的功能和小鼠环路CA3-CA1的LTP；3）Bod1敲除影响了PP2A-CaMKII信号通路，调控NAMA受体内吞；4）Bod1蛋白在敲除小鼠海马脑区过表达后对认知功能障碍的延缓和改善作用。.课题意义：进一步揭示智力障碍的发病机制，为智力障碍的预防和治疗提供新的药物靶点和研究思路。