放射诱导小胶质细胞自我更新紊乱机制研究

Radiation induced cognitive dysfunction affect quality of life of brain tumor patients who received brain irradiation, seriously. Microglia is the potential target to prevent radiation induced cognitive dysfunction. Our previous study found that microglia of rat hippocampus increase at the early stage and decrease at the late stage after brain irradiation. And extensive morphological changes were observed at the late stage after large dose brain irradiation. The mechanism of self-renew of microglia affected by radiation is unknown. We hypotheses that IL-1 increased at the early stage promote the proliferation of microglia, and microglia apoptosis after active cause the number decrease and dysfunction at the late stage. To verify our hypotheses, we will explore whether the increased microglia come from the proliferation of resident microglia or recruit of blood derived monocytes, and whether inhibit IL-1 pathway could affect the proliferation of microglia. And we will detect the apoptosis and proliferation ability of microglia after brain irradiation, and explore whether inhibit microglia active or deprive microglia could prevent the decrease of microglia. Finally, we will explore the engulf function of residual microglia, and re-active after re-radiation and LPS stimulation. This study will clarify the mechanism of microglia self-renew disorder after radiation, and provide new target for intervening brain radiation injury.

放射性认知功能障碍严重影响脑肿瘤患者放疗后的生活质量，小胶质细胞是其主要潜在干预靶点。我们的前期研究发现：脑部照射后，大鼠海马区小胶质细胞在早期数量明显增多；而后期数量显著减少并伴随形态学改变。我们假设放射影响小胶质细胞动态变化的机制为：早期由于炎症因子IL-1的刺激，小胶质细胞大量增殖，引起数量增多；小胶质细胞过度活化后凋亡引发其后期数量减少及其功能改变。为验证此假设，我们将研究：(1)脑部照射早期小胶质细胞增加的来源是脑实质内源性小胶质细胞增殖还是外周髓源性单核细胞浸润，阻断IL-1通路是否影响小胶质细胞增殖；(2)照射诱导小胶质细胞凋亡及对其干细胞样细胞的影响，明确照射后期小胶质细胞数量减少的原因；(3)照射后残存小胶质细胞的吞噬功能变化，及能否被再激活。本课题将阐明放射后小胶质细胞的变化规律及其机制，为放射性脑损伤的干预提供新靶点。

放疗是治疗脑原发肿瘤和转移性脑肿瘤的有效手段之一。但放疗导致的放射性认知功能障碍严重影响患者的生活质量。小胶质细胞与神经发生、死亡或凋亡神经元的吞噬作用、神经回路的形成等相关，是放射性认知功能障碍的重要靶细胞之一，但其发生变化的具体机制尚不清楚。我们研究发现，照射后小胶质细胞有时间剂量依赖性，即低剂量照射导致小细胞数量持续减少；中剂量照射早期小胶质细胞数量减少，后恢复至正常水平；而大剂量照射早期小胶质细胞数量减少，后期增多。并且，大剂量照射后小胶质细胞呈现分枝少的“枯枝样”，再照射也未能被激活，提示功能障碍。此外，我们发现与小胶质细胞关系密切的神经元细胞在受照射后，长度降低且线粒体形态和功能发生显著变化。本课题为进一步探究小胶质细胞及小胶质细胞-神经元相互作用在放射性脑损伤机制提供了新的方向与机制。