伴有皮质下梗死和白质脑病的常染色体显性遗传性脑动脉病（CADASIL）是由于Notch3基因发生突变所致。作为一个调控基因转录表达的受体，Notch3对下游基因、蛋白、miRNA的表达调控无疑会对CADASIL的分子病理过程提供重要线索。目前为止，Notch3下游miRNA表达变化未见报道。在前期实验中，我们在CADASIL病例和Notch3-突变鼠里发现miR-181a表达升高及其靶基因（Kcnmb1、Lrrfip1）表达下降的现象；而且有证据提示Notch3-RBPJ通路对miR-181a可能有负调控作用。在此基础上，我们一方面将深入研究Notch3-RBPJ通路调控miR-181a的分子机制；另一方面将在活体动物体内解析miR-181a及其靶基因对血管功能的调节作用；最后观察miR-181a阻断剂能否减轻CADASIL模型小鼠的疾病表型。本项目将为CADASIL提供新的分子治疗策略。

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is caused by mutations in Notch3 gene encoding a transmembrane receptor Notch3. However, the functional nature of the Notch 3 mutations causing CADASIL and their mechanistic connection to small-vessel disease remain enigmatic. Given the importance of Notch3 signaling in regulating gene expression, the downstream expression profile of mRNA, protein and miRNA of Notch3 signaling will provide insight into the molecular pathogenic mechanism of CADASIL. However, so far, the influence of Notch 3 mutations on the miRNA expression profile in the brain has not been investigated. We recently established that, in CADASIL patients biopsies and in R90C mutation knock-in mice (TgNotch3R90C), expression level of miR-181a is markedly upregulated while two targets of Notch3 (Kcnmb1、Lrrfip1) were significantly down-regulated. Additional evidence suggested a negative regulatory role of Notch3-RBPJ signaling on miR-181a expression. Based on these results, in this proposal, we are going to further investigate the molecular mechanism of Notch3-RBPJ signaling on miR-181a expression. Moreover, functional role of miR-181a and its targets on vascular function in mice (in vivo) will be dissected. Finally, miR-181a antagomir（anti-miR-181a）will be injected into R90C mutation knock-in mice (TgNotch3R90C) to assess if blocking miR-181a would alleviate CADASIL phenotype. Our project will provide a new therapeutic tool for the control of CADASIL.