P2Y1受体-STAT3信号通路介导的星形胶质细胞活化在海马区放射损伤中的作用及机制研究

大脑海马区放射损伤是放射后认知功能下降的重要原因。我们的前期发现，放射后海马区小胶质细胞诱导星形胶质细胞P2Y1受体表达下调，继而发生依赖STAT3的星形胶质细胞活化及功能表型转化，同时介导海马区突触可塑性及神经生成的关键分子Wnt7a发生表达下调，并伴随海马CA3区兴奋性突触数量减少。此外，以药物抑制P2Y1受体可加剧放射诱导的海马区星形胶质细胞活化、Wnt7a下调及空间认知能力下降。由此我们推测，P2Y1受体-STAT3信号可能在海马区星形胶质细胞激活及放射损伤中发挥重要作用。我们拟通过原代细胞培养、离体海马培养、动物行为学等体内外方法，研究放射后星形胶质细胞P2Y1受体下调及STAT3激活的分子机制，明确P2Y1受体-STAT3信号在介导放射后海马区星形胶质细胞活化、突触可塑性下降及神经生成抑制中的作用。本项目的完成将揭示海马区放射损伤新的重要机制，为放射损伤防护提供新的理论依据。

Radiation injury in hippocampus is an important cause for radiation-induced cognitive decline. We have been previously demonstrated that microglia induces downregulation of P2Y1 receptor in hippocampal astrocytes. Then STAT3-dependent activation and phenotype transformation of astrocyte occurred. We also found that wnt7a, a critical regulator of synapse plasticity and neurogenesis in hippocampus, is downregulated. This is coupled with a decreased number of excitatory synapse in CA3. Pharmacological inhibition of the P2Y1 receptor further promotes radiation-induced activation of astrocyte, downregulation of wnt7a and decline of spatial cognitive ability. Therefore it can be deduced that P2Y1 receptor-STAT3 signalling may play a critical role in activating astrocyte and hippocampus injury. To test the hypothesis, we will first explore the mechanisms of downregulation of P2Y1 receptor and its role in promoting activation of STAT3. Secondly, we will detect the role of P2Y1 receptor- STAT3 signalling in promoting radiation-induced activation of hippocampal astrocyte, decline of synapse plasticity and neurogenesis. This would contribute to better understanding the mechanism of radiation injury in hippocampus and provide new strategy for radiation protection.