脑动静脉畸形（bAVM）是一种局部颅内动、静脉血管异常相连的疾病，尚无有效的药物治疗bAVM。bAVM的发病机制尚不明确。激活内质网定位的SGMR1的分子伴侣功能可辅助内质网正常折叠和分泌活性蛋白。申请人前期发现SGMR1在bAVM患者畸形血管中表达显著下调，细胞中激活SGMR1影响平滑肌细胞的增殖和胞外BDNF的水平。BDNF是一种重要的神经因子。文献报道MMP9上调可促进proBDNF到BDNF的转化，但在bAVM患者血清中：MMP9表达水平显著上调，proBDNF含量不变，但BDNF表达水平却下调。因此我们推测SGMR1的激活可能介导MMP9在ER上的正常折叠。本项目将在细胞层面验证该假设，探索是否有其他蛋白酶参与该过程；完成HHT1型bAVM小鼠模型的构建，在动物水平确定SGMR1激动剂是否有潜力作为治疗bAVM的新型药物。

Brain arteriovenous malformations (bAVM) are characterized by vascular focal lesions of enlarged, tangled vessels that shunt blood from arteries directly to veins. At present, there is no specific drug for it. What’s more, the pathogenesis of bAVM remains poorly understood. SGMR1, as a molecular chaperone, locates on ER membrane and assists in protein folding and secreting. Our previous results demonstrated downregulation of SGMR1 in bAVM specimens compared to normal intracranial vessels and superficial temporal arteries. In addition, we found that active SGMR1 involves in VSMC (vescular smooth muscle cell) proliferation and BDNF secretion. BDNF is considered as an important neurotrophic factor. It has been reported that MMP-9 is one of the metalloproteinases that can promote precursor BDNF (proBDNF) conversion into mature BDNF. Nevertheless, we found that serum proBDNF level remains stable, MMP9 was significantly upregulated while BDNF was markedly downregulated in bAVM patients. Thus, we assume that the activation of SGMR1 may mediate the folding of MMP9 on ER. This project aims to, (i) investigate the molecular chaperone function of SGMR1 in bAVM on mediating MMP9 misfolding which regulates the conversion of proBDNF to BDNF; (ii) to build a HHT1 bAVM model mice, and test whether SGMR1 agonist was useful in alleviating bAVM disorder symptoms or with effective treatment in bAVM mice. The project will mainly focus on investigating the molecular mechanism, supplying potential clinical drug targets and effective pharmaceuticals for bAVM treatment.