PGC-1α在应激性脑损伤中的作用以及EGCG对其调控机制研究

Nowadays, there are increasing stress-induced cerebral dysfunctions, and more attentions were paid to the study about the efficient protections against stress, so as to ameliorate the victims' mental impairment and to improve their life qualities. The cerebrum is badly vulnerable to suffer from energy metabolic disorder resulted from stress, consequently led to cerebral dysfunctions. The previous study of our research team suggested that (-)-epigallocatechin gallate (EGCG) could evidently protect cerebrums against stress-induced injuries. And during exploring the detailed molecular mechanisms of EGCG on signal transduction, the expression of peroxisome proliferators-activated receptor-γ coactivator-1α (PGC-1α) in brain was shown to be changed. As a master regulator of energy metabolism, PGC-1α can enhance mitochondrial biogenesis to maintain energy requirement of different tissues. However, little was known about the bioactivities of PGC-1α in cerebrum. So this study will be conducted to examine the effects of PGC-1α on stress-induced cerebral dysfunctions. Moreover, it'll be going to explore EGCG's role in affecting PGC-1α expression and in regulating the activation of PGC-1α within different cerebral domains. In addition, the relationship between the modulation of EGCG on some signal proteins and PGC-1α will be also investigated in this research. Then the related results will be testified in stress model of cultured neurons in vitro. Thereby, this research will clarify the related molecular mechanisms of stress-induced cerebral dysfunctions, and will determine the target-molecules in central nervous system by which EGCG practices its protective effects. These proofs will pave the way for further research of EGCG as protective substance against stress-induced cerebral damages. And it also will provide a novel method to explore the biological functions and potential applicability of other natural bioactivators.

近年来应激性脑损伤的发生逐年增高，严重影响罹患者的身心健康和生活质量，对应激性脑损伤的防护研究成为相关领域的重点问题。脑对能量需求敏感，而应激引起能量代谢紊乱极易导致应激性脑损伤。本项目组前期研究显示，EGCG可影响线粒体活性，对应激性脑损伤有显著保护作用，而且在探讨EGCG对细胞信号转导调控时观察到PGC-1α在脑中的表达发生改变。PGC-1α作为能量代谢的关键调控因子，能调控心脏、骨骼肌等的线粒体合成以维持组织的能量需求，但有关PGC-1α在脑中的作用知之甚少。本项目拟采用在体和离体实验，通过过表达和抑制表达PGC-1α探讨其对应激性脑损伤的作用；并探讨EGCG对PGC-1α表达和功能激活的影响及调控机制，阐明EGCG对信号蛋白的调控和PGC-1α之间的相关关系。从而揭示应激性脑损伤发生的分子机制，明确EGCG的中枢作用靶点，进一步深化以天然活性物质EGCG进行应激性脑损伤防护的研究。

近年来应激性脑损伤的发生逐年增高，严重影响罹患者的身心健康和生活质量，对应激性脑损伤的防护研究成为相关领域的重点问题。脑对能量需求敏感，而应激引起能量代谢紊乱极易导致应激性脑损伤。本项目组前期研究显示，EGCG可影响线粒体活性，对应激性脑损伤有显著保护作用，而且在探讨EGCG对细胞信号转导调控时观察到PGC-1α在脑中的表达发生改变。PGC-1α作为能量代谢的关键调控因子，能调控心脏、骨骼肌等的线粒体合成以维持组织的能量需求，但有关PGC-1α在脑中的作用知之甚少。本项目组在前期研究的基础上，采用在体实验和离体实验相结合的方法，探讨了能量代谢的关键调控因子PGC-1α在应激性脑损伤中的表达变化情况及其对应激性脑损伤的调节作用；并探讨了EGCG对PGC-1α表达和功能激活的影响及调控机制。结果显示，在应激条件下脑组织中不同脑区的PGC-1α表达与正常动物相比出现显著变化，尤其是作为应激调节中枢的海马组织，表现最为显著。而给予EGCG干预后应激动物的PGC-1α表达出现明显提高。在离体实验中，EGCG干预可明显提高应激神经元的存活率和ATP含量，并显著增强应激神经元的信号蛋白表达及其磷酸化水平。通过对海马神经元进行表达质粒转染实现PGC-1α的表达，结果表达PGC-1α细胞在应激情况下的细胞存活率、ATP含量以及细胞信号蛋白PKC、AKT和ERK1/2的表达均较应激组显著增加。而且PGC-1α表达细胞在皮质酮刺激并EGCG干预下其信号蛋白的表达与EGCG干预组相近，均显著高于应激组。本研究提示PGC-1α在应激性脑损伤中具有重要作用，对能量代谢和细胞信号转导发挥着重要的调节作用，改变PGC-1α的表达能够增强神经元的抗应激能力，并对EGCG防护应激性神经损伤产生增强或协同作用。该研究对进一步深化以天然活性物质EGCG进行应激性脑损伤防护措施的探讨提供了重要的科学依据。并为其他天然生物活性物质的研究和应用提供一种新的思路。