NDRG2通过抑制胶质细胞过度活化保护次声性脑损害的机制研究

Infrasound is a kind of low-frequency noise and exists ubiquitously around our environment. Brain is one of the vulnerable target organs to infrasound, and infrasound with a certain pressure and frequency can cause permanent brain injury. Our previous study showed that infrasound activated glial cells excessivley, and subsequently glial cell-mediated inflammation caused neuronal cell death. Therefore, glial inhibition will be no doubt helpful for attenuatinginfrasound-induced brain impairment. Our lateststudy showed that after infrasound exposure, the expression of NDRG2, a well-known tumor suppressor, mainly distributed in astrocytes and microglia,was significantly downregulated in rat brain. Based on the evidence that NDRG2 could decrease the activities of proliferation-associated factor AP-1 and inflammation-associated nuclear transcription factor NF-κB, we hypothesize that NDRG2downregulation may activateglial cell proliferation and glial cell-mediated inflammation to involvein infrasound-induced brain injury via de-repressing AP-1 and NF-κB activity. In order to clarify the relationships among NDRG2, glial activation and neuronal injury, in this projectglial antagonists will used to explore the effects of glial inhibition on neuronal survival. Viral vector transfectionwill be employed in vivo and in vitro to investigate the effects of NDRG2 expression alteration onglial cell proliferation and inflammation, and on neuronal cell death and brain injury. Our results will provide the original data for the mechanisms underlying infrasonic damage and theoretical basis for medical protection against infrasound-induced brain injury.

次声是一种低频噪音，在周围环境中广泛存在。脑是次声伤害的重要易损器官，一定强度的次声可造成脑的不可逆损伤。研究发现，次声可过度激活脑内的胶质细胞，其介导的炎症反应可造成神经元死亡，提示:抑制胶质细胞过度活化将有助于减轻次声性脑损害。本课题组发现，次声暴露后大鼠脑内NDRG2的表达水平明显降低，且定位于小胶质细胞和星形胶质细胞。结合已有报道：NDRG2可抑制促细胞增殖因子AP-1和炎症调控关键因子NF-κB，我们提出假说：次声暴露后，NDRG2的降低导致对AP-1和NF-κB抑制减弱，使得胶质细胞增殖及其介导的炎症反应增强，从而造成神经元损伤。为此，本课题拟采用药物干预等手段，观察抑制胶质细胞活化对神经元存活的影响；利用病毒载体感染等方法，体内和体外特异地在胶质细胞中改变NDRG2表达水平，观察其对胶质细胞增殖活化、炎症反应及对神经元死亡和脑损伤的影响，为次声损伤防护提供新的思路和治疗靶点。

次声是一种低频噪音，在周围环境中广泛存在。脑是次声伤害的重要易损器官，一定强度的次声可造成脑的不可逆损伤。研究发现，次声可过度激活脑内的胶质细胞，其介导的炎症反应可造成神经元死亡，提示：抑制胶质细胞过度活化将有助于减轻次声性脑损害。本课题组发现，次声暴露后大鼠脑内NDRG2的表达水平明显降低，且定位于小胶质细胞和星形胶质细胞。结合已有报道：NDRG2可抑制促细胞增殖因子AP-1和炎症调控关键因子NF-κB，我们提出假说：次声暴露后，NDRG2的降低导致对AP-1 和NF-κB 抑制减弱，使得胶质细胞增殖及其介导的炎症反应增强，从而造成神经元损伤。.为此，本项目在国家自然科学基金（No. 31370834）资助下开展了以下工作：.（1）次声暴露后大鼠脑内NDRG2表达的变化；（2）次声暴露后大鼠脑内胶质细胞增殖活化的情况；（3）次声暴露后大鼠脑内神经元损伤的情况；（4）次声暴露后培养胶质细胞NDRG2的表达变化；（5）次声暴露后培养胶质细胞的活化情况；（6）次声暴露后胶质细胞培养上清对神经元的损伤作用；（7）次声暴露后培养胶质细胞炎症调控关键因子NF-κB的核转位情况。利用形态学和细胞生物学等方法发现：（1）暴露于16Hz, 130dB次声后，大鼠的学习记忆能力下降；（2）次声暴露后大鼠脑内胶质细胞增殖并活化，但NDRG2的表达降低；（3）次声暴露后大鼠海马区死亡神经元数目增加；（4）次声暴露后大鼠培养胶质细胞增殖并活化，但NDRG2的表达降低；（5）培养胶质细胞上清中TNF-α和IL-1β水平增加，同时死亡神经数目增加；（6）次声暴露后胶质细胞NF-κB核转位增多。.基于以上研究结果，我们提出次声神经损伤的新机制：次声可通过下调NDRG2表达，促进胶质细胞增殖并激活胶质细胞，进而通过释放多种炎性细胞因子损伤神经元。因此，我们基本完成了本项目大部分工作，揭示次声神经损伤的可能性机制，为次声损伤防护提供新的思路和治疗靶点。.