基于SIRT3-CypD信号通路探讨GDF11对脑出血的神经保护作用及机制研究

Intracerebral hemorrhage (ICH), as a common hemorrhagic stroke, causes high morbidity and mortality in clinic. So far, there is no effective treatment to improve the prognosis of ICH. Oxidative stress(OS) after ICH is believed as a core factor causing secondary cerebral deficit, while mitochondrial dysfunction of neurons is an important mechanism responsible for OS damage. As reported by recent researches, GDF11 has protective effects of multiple organ functions against OS, but few data are mentioned in the ICH fields. In previous study, we found that exogenous injection of GDF11 could relieve the impairment of neural and mitochondrial function in ICH rats, though the mechanism is still unclear. Among anti-OS mechanisms, SIRT3-CypD signal pathway is proved as a key role in maintaining the mitochondrial functional homeostasis. However, what is the inherent relationship between the regulation of this pathway and anti-OS effect of GDF11 still remains to be further explored. Herein, our research aims to explore the protective effect of GDF11 in neurons and mitochondria after ICH by establishing ICH model in vitro and in vivo. By observing the changes of multiple levels including molecular level, cell organ level, cell level, tissue level and neuro-behavior level with or without GDF11, we will reveal mechanism of GDF11 in regulation of SIRT3-CypD signal pathway and its protective role of mitochondria against OS to improve neurological function after ICH.

脑出血是临床上常见的卒中类型，其起病骤然且预后凶险，具有很高的致残率与死亡率。目前尚无有效治疗方式能显著改善脑出血患者的预后。大量证据表明，脑出血后氧化应激反应是继发脑功能废损的核心因素，而神经线粒体的活性异常与功能障碍是该损伤机制的重要环节。近年研究发现，GDF11具有抗氧化应激与多器官功能保护作用，但相关研究尚未涉及脑出血领域。申请者前期发现，外源性注射GDF11后可缓解大鼠脑出血的神经与线粒体功能损伤，但机理尚不清楚。在神经抗氧化应激机制中，SIRT3-CypD信号通路被证实对维持线粒体功能稳态十分关键。然而该通路的调控是否与GDF11的抗氧化应激作用存在内在联系，还有待进一步探索。因此，该项目拟通过构建体内、体外脑出血模型，从分子层面、细胞器层面、细胞层面、组织层面和整体行为功能层面多层次探讨GDF11对SIRT3-CypD通路的调控作用与脑出血后抗氧化应激神经保护机制。

脑出血是临床上常见的卒中类型，其起病骤然且预后凶险，具有很高的致残率与死亡率。目前尚无有效治疗方式能显著改善脑出血患者的预后。大量证据表明，脑出血后氧化应激反应是继发脑功能废损的核心因素，而神经线粒体的活性异常与功能障碍是该损伤机制的重要环节。近年研究发现，GDF11具有抗氧化应激与多器官功能保护作用，但相关研究尚未涉及脑出血领域。申请者前期发现，外源性注射GDF11后可缓解大鼠脑出血的神经与线粒体功能损伤，但机理尚不清楚。在神经抗氧化应激机制中，SIRT3-CypD信号通路被证实对维持线粒体功能稳态十分关键。然而该通路的调控是否与GDF11的抗氧化应激作用存在内在联系，还有待进一步探索。因此，该项目拟通过构建体内、体外脑出血模型，从分子层面、细胞器层面、细胞层面、组织层面和整体行为功能层面多层次探讨GDF11对SIRT3-CypD通路的调控作用与脑出血后抗氧化应激神经保护机制。