多重性脑创伤后miRNAs对海马神经发生与胶质细胞发生的调控机制

Chronic traumatic encephalopathy (CTE) is a long-term progressive neurodegenerative disease characterized by abnormal neurogenesis and gliogenesis, neuronal death, neuronal circuitry malfunction, and synaptic plasticity impairment which are similar to those seen in other neurodegenerative diseases, including Alzheimer’s disease. Latest evidences suggest that the risk of developing CTE is significantly increased in sports players and military personnel who have been exposed to repetitive trauma brain injury. Currently, we still know very little about the epigenetic mechanisms underlying the pathological changes of CTE. This proposed project will continue our investigation on this subject, in which we have successfully developed a mouse model of CTE, and identified a subset of dysregulated miRNAs in the hippocampus following trauma brain injury. We plan to (1) elucidate the molecular mechanisms of miRNAs in regulating the abnormal neurogenesis and gliogenesis in the hippocampus following repetitive mild closed head injury; and (2) explore the possibility and new approaches to treat CTE by manipulating the expressions of miRNAs and/or key molecules of their signaling pathways in vivo. This study will shed a light on understanding the role of miRNAs in the pathological changes in the hippocampus following traumatic brain injury, and might have implications for developing novel and efficacious therapeutic interventions for preventing development of CTE or halting disease progression.

多重性脑创伤患者常常会发展为慢性创伤性脑病等渐进性神经退行性疾病，脑创伤病人的海马往往呈现出神经发生与胶质细胞发生异常、神经元凋亡、神经环路异常、突触传递和突触可塑性受损等生理病理性的改变。然而，这些生理病理性改变背后的分子调控机制尚未阐明清楚。本项目旨在继续深入项目申请者在这方面的研究，以前期在创伤海马中鉴定出的异常表达的miRNAs为突破口，研究多重性脑创伤后异常表达的miRNAs影响海马神经干细胞增殖与分化、神经元成熟过程的分子机理；阐明异常表达的miRNAs对神经胶质细胞发生的调控机制；通过体内干预miRNAs或其信号通路中的关键信号分子，探索治疗慢性创伤性脑病的可能性与途径。本研究对揭示多重性脑创伤后神经发生与胶质细胞发生异常的表观遗传调控机制具有重要意义，也将为寻找治疗创伤性脑病的分子靶标和策略提供实验依据。

多重性脑创伤患者常常会发展为慢性创伤性脑病等渐进性神经退行性疾病，脑创伤病人的海马往往呈现出神经发生与胶质细胞发生异常、神经元凋亡、神经环路异常、突触传递和突触 可塑性受损等生理病理性的改变。然而，这些生理病理性改变背后的分子调控机制尚未阐明清楚。本项目旨在继续深入项目申请者在这方面的研究，以前期在创伤海马中鉴定出的异常表达的microRNAs为突破口，系统研究了多重性脑创伤后异常表达的miRNAs在海马神经发生、胶质增生中的功能与分子机理。发现miR-137、let-7a为脑创伤早期潜在的分子标记，发现抑制PDE10A与EZH2能有效改善脑创伤小鼠的学习认知能力与焦虑行为。