Role of THSD1 and its Disease Causing Variants in Intracranial Aneurysm

颅内动脉瘤(IA)是大脑动脉壁中的一个薄弱区域，导致 异常扩张和可能破裂导致蛛网膜下腔出血(SAH)。尽管接受了治疗 进展，动脉瘤破裂的死亡率超过40%，只有一半的幸存者返回 为了独立的生活。仅在美国，就发生了大约30,000例SAH病例 每年一次。在破裂之前，IAS通常是无症状的，通常不被注意到。什么时候 在破裂前进行识别和治疗，存活率显著提高。因此，很早 IAS的发现、适当监测和及时治疗在以下方面至关重要 预防残疾和过早死亡。我们的研究小组最近发现了罕见的变异 家族性和散发性IA患者的血栓反应蛋白1型结构域蛋白1(THSD1) 以及使用人类遗传学和动物模型的SAH病例。THSD1是一种特征不佳的 其表达主要局限于内皮细胞的基因。在这里，我们试图澄清 THSD1在脑血管内皮细胞中的关键作用，使用小鼠基因敲除和人类基因敲除 脑血管内皮细胞。我们将检验有害的THSD1变异体损害 扰乱局部粘连导致信号转导失调的内皮细胞功能 通过粘着斑激酶(FAK)介导。这一假设得到了我们初步的支持 包括THSD1人脑微血管无偏全球通路分析的数据 内皮被击倒的细胞。我们预计这项研究将在一定程度上阐明 导致IA形成和破裂的机制。此外，还将有新的发现 对颅内动脉瘤的早期诊断和治疗具有潜在的临床意义， 从而降低发病率和死亡率。这项工作对血管也有更广泛的影响。 生物学作为新的证据表明Thsd1参与内皮屏障功能和保护 动脉粥样硬化性和出血性病变中的血管系统。

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.