Sirolimus通过干预mTOR通路降低脑动静脉畸形破裂出血风险的研究

目前脑动静脉畸形治疗方式给患者带来的神经功能损伤是严重的临床问题，对于新的治疗方式的需要迫在眉睫。我们前期研究发现Sirolimus能够明显改善脑动静脉畸形内皮细胞的血管形成功能，根据目前脑动静脉畸形血管内皮细胞KRAS突变学说，我们提出假说：Sirolimus通过抑制血管内皮生长因子表达来介导较少血管生成，进而减小脑动静脉畸形破裂出血风险。本课题拟利用Sirolimus干预脑动静脉畸形血管团内皮细胞体外模型以及小鼠体内模型，明确脑动静脉畸形血管内皮细胞特性，KRAS基因表达水平，以及mTOR信号通路三者之间的关系，从分子、细胞以及动物水平探讨Sirolimus通过mTOR通路降低脑动静脉畸形出血风险的可能机制。本项目旨在阐明脑动静脉畸形内皮细胞结构及分子特性的基础上，利用药物干预降低脑动静脉畸形破裂出血，为脑动静脉畸形的药物治疗提供新的理论依据。

The neurological damage caused by a cerebral arteriovenous malformation (cerebral AVM) is a serious clinical problem, and needs to be carefully considered. Our previous studies showed that Sirolimus significantly improved angiogenic functions of endothelial cells in a cerebral AVM. Based on the current KRAS mutation theory of vascular endothelial cells, we propose a hypothesis that Sirolimus can reduce the formation of vasculature by inhibiting the expression of vascular endothelial growth factor, leading to the reduction of the risk of rupture of a cerebral AVM. In the current proposal, we attempt to use Sirolimus to intervene vascular endothelial cells in in vitro and in vivo models of a cerebral AVM to explore the relationship between vascular endothelial cell characteristics, KRAS gene expression levels, and mTOR singling pathways. We will discuss the possible molecular mechanisms by which Sirolimus reduces the risk of bleeding from a cerebral AVM through the mTOR pathway in cellular and animal levels, respectively. The purpose of this study is to clarify the cellular and functional characteristics of endothelial cells of a cerebral AVM, and to reduce the risk of rupture of a cerebral AVM by a drug intervention. Our study will provide with a new experimental basis for therapeutic approaches to the neurological damage caused by a cerebral AVM.