Role of THSD1 and its Disease Causing Variants in Intracranial Aneurysm

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An intracranial aneurysm (IA) is a weakened area in a cerebral artery wall that leads to abnormal dilation and may rupture causing subarachnoid hemorrhage (SAH). Despite treatment advances, the mortality of aneurysmal rupture is over 40%, and only one-half of survivors return to independent life. In the United States alone, approximately 30,000 SAH cases occur annually. Prior to rupture, IAs are usually asymptomatic and typically go unnoticed. When identified and treated before rupture, survival rates dramatically improve. Therefore, early detection, proper monitoring, and timely treatment of IAs are of paramount importance in preventing disability and premature death. Our research team recently implicated rare variants in thrombospondin-type 1 domain-containing protein 1 (THSD1) in both familial and sporadic IA and SAH cases using human genetics and animal models. THSD1 is a poorly characterized gene whose expression is largely restricted to endothelial cells. Here, we seek to elucidate the key roles of THSD1 in brain vascular endothelial cells, using both a mouse knockout and human brain endothelial cells. We will test the hypothesis that harmful THSD1 variants impair endothelial cell function by perturbing focal adhesions leading to dysregulated signaling mediated through focal adhesion kinase (FAK). This hypothesis is supported by our preliminary data that includes an unbiased global pathway analysis of THSD1 human brain microvascular endothelial knockdown cells. We anticipate that this research will elucidate in part the underlying mechanism that leads to IA formation and rupture. Additionally, new discoveries will be made with potential clinical impact for the early diagnosis and treatment of intracranial aneurysms, thereby reducing morbidity and mortality. This work also has broader implications in vascular biology as emerging evidence implicates Thsd1 in endothelial barrier function and in protection of the vasculature in atherosclerotic and hemorrhagic lesions.