Functional Validation of Intracranial Aneurysm Risk Genes

颅内动脉瘤（IA）是美国和全球的一个重大健康问题。它们的破裂导致 颅内出血，具有毁灭性的结局：30%的颅内动脉瘤破裂患者在术后一个月内死亡。 50%的幸存者留下了严重的神经功能缺损，需要长期护理。在我们 在之前的研究中，我们完成了一系列全基因组关联研究（GWAS）， IA风险基因座含有候选IA风险基因。我们现在打算研究选择的生物学意义 在人内皮和血管平滑肌细胞系中使用基因组编辑的候选基因，并验证 这些发现在斑马鱼和小鼠，两个模式生物是理想的遗传操作， 脑血管系统的分析。这些研究将建立基因调控的机制， 剂量可能会增加动脉瘤形成的风险，测试他们影响血管的假设 稳态和血管张力调节。如果成功，这些研究将刺激未来的研究， 以及IA的分子信息治疗方法。

Intracranial aneurysms (IA) represent a significant health issue in the US and worldwide. Their rupture leads to intracranial hemorrhage, with devastating outcomes: 30% of patients with ruptured IA die within a month of the initial event, and 50% of survivors are left with severe neurological deficits requiring long-term care. In our previous studies, we completed a series of genome-wide association studies (GWAS), which identified several IA risk loci containing candidate IA risk genes. We now propose to investigate the biological significance of select candidate genes using genome editing in human endothelial and vascular smooth muscle cell lines, and validate these findings in zebrafish and mouse, two model organisms that are ideal for genetic manipulations and analyses of brain vasculature. The proposed studies will establish the mechanisms by which modulation of gene dosage may enhance risk of aneurysm formation, testing to the hypothesis that they impact vascular homeostasis and vessel tone regulation. If successful, these studies will stimulate future research into rational and molecularly informed therapeutic approaches for IA.