RIN3 rs10498633在阿尔茨海默病发生发展中的作用及其机制研究

我们已发表的研究发现AD模型小鼠脑内异常高表达的RIN3蛋白可增加毒性C99的产生及tau磷酸化（pTau），与AD的发生发展密切相关。多项研究揭示RIN3上游非编码区rs10498633为AD风险位点，我们也发现该位点致AD风险升高，近期我们发现rs10498633G>T显著增强RIN3表达，但机制不清。生物信息学预测发现rs10498633所在序列可能为RIN3远端增强子，远端增强子主要通过结合转录因子（TF）调控启动子活性影响转录，分析rs10498633的TF结合情况显示，多种TF在rs10498633T和G间具有不同的结合倾向性。因此，我们推测此变异通过影响TF与增强子的结合，上调RIN3启动子的转录活性引起RIN3表达升高，进一步导致C99和pTau的增多而增加AD风险。本项目我们将通过体内外实验验证我们的假说，探讨rs10498633在AD发生、发展中的作用及可能机制。

Our published research found the abnormally upregulated RIN3 in the brain of AD mice could increase the production of toxic C99 and tau phosphorylation, which are closely related to the occurrence and development of AD. A number of studies revealed that rs10498633, located in the upstream non-coding region of RIN3, is an AD risk locus. We also found that this site increases the risk of AD, besides, rs10498633 G>T significantly enhances the expression of RIN3, but the mechanism is still unclear. Through bioinformatic analysis, we found that rs10498633 is located in a highly probable distal enhancer region of RIN3. The distal enhancer mainly affects transcription by binding transcription factor (TF) to regulate promoter activity. Analysis of rs10498633 TF binding sites showed that a variety of TFs have different binding propensities between rs10498633 T and G. Therefore, we speculate that rs10498633 affects the binding of TF and enhancer and upregulates the transcriptional activity of the RIN3 promoter to increase the expression of RIN3, which further leads to an increase in Aβ and phosphorylated tau, increasing the risk of AD. In this project, we will verify the hypothesis through in vivo and in vitro experiments, and explore the role and possible mechanism of rs10498633 in the occurrence and development of AD.