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.

Intracranial aneurysms are balloon-like vascular dilations of the intracranial arteries that rupture leading to hemorrhagic stroke with catastrophic, often fatal, outcomes. The genetic architecture of intracranial aneurysm is complex. In the last decade, we have conducted genetic studies that identified a number of candidate genes that confer susceptibility to intracranial aneurysm formation. Our proposal will use cellular and animal models to investigate the contributions of these candidate genes to aneurysm formation. The proposed research is relevant to public health because understanding the mechanisms of aneurysm formation and validating their genomic architecture will provide the necessary background to develop targeted therapeutic approaches in future studies.