Role of THSD1 and its Disease Causing Variants in Intracranial Aneurysm

THSD1 及其致病变异在颅内动脉瘤中的作用

• 批准号: 10379334
• 负责人: John Patrick Hagan
• 金额: $ 33.69万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10379334
• 关键词: AKT Signaling Pathway; Adult; Affect; Age; Age-Months; American; Animal Model; Apoptosis; Area; Biochemical; Biological Assay; Biological Models; Biology; Blood Vessels; Brain; Caliber; Cell physiology; Cells; Cerebral hemisphere hemorrhage; Cerebrovascular system; Cessation of life; Clinical; Data; Defect; Disease; Distal; Early Diagnosis; Early treatment; Endothelial Cells; Endothelium; Etiology; Extracellular Matrix; Family; Focal Adhesion Kinase 1; Focal Adhesions; Frequencies; Functional disorder; Genes; Genetic; Genetic Models; Genetically Engineered Mouse; Goals; Hemorrhage; Human; Human Genetics; Hypertension; Impairment; Incidence; Integrins; Internal carotid artery structure; Intracranial Aneurysm; Kinetics; Knockout Mice; Lead; Lesion; Life; Literature; Mediating; Mediator of activation protein; Molecular; Monitor; Morbidity - disease rate; Mus; Mutant Strains Mice; PECAM1 gene; Pathway Analysis; Pathway interactions; Pericytes; Permeability; Population; Prevalence; Prevention; Property; Proteins; Reporting; Research; Risk Factors; Role; Rupture; Ruptured Aneurysm; Signal Pathway; Signal Transduction; Smooth Muscle; Stroke; Subarachnoid Hemorrhage; Subarachnoid Space; Survival Rate; Survivors; Talin; Testing; Therapeutic Intervention; Thick; Thrombospondins; Time; United States; Variant; Vascular Endothelial Cell; Work; Zebrafish; base; brain endothelial cell; cerebral artery; cerebrovascular; cerebrovascular pathology; disability; disease phenotype; effective therapy; exome sequencing; genome-wide linkage; improved; in vivo; knock-down; loss of function; mortality; novel; premature; prevent; proband; rare variant; rho; shear stress; stroke victims; tool; transcriptome sequencing

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.

颅内动脉瘤（IA）是脑动脉壁中的弱化区域，导致 异常扩张并可能破裂导致蛛网膜下腔出血（SAH）。尽管接受了治疗 随着技术的进步，动脉瘤破裂的死亡率超过40%，只有一半的幸存者返回 独立生活。仅在美国，就有大约30，000例SAH病例发生 每年。在破裂之前，IA通常是无症状的，通常不被注意。当 在破裂前发现和治疗，存活率大大提高。因此早期 检测、适当监测和及时治疗IA对于 预防残疾和过早死亡。我们的研究团队最近发现了 在家族性和散发性IA中，血小板反应蛋白1型含结构域蛋白1（THSD 1） 和SAH病例中使用人类遗传学和动物模型。THSD 1是一种表征不佳的 其表达主要限于内皮细胞的基因。在这里，我们试图阐明 THSD 1在脑血管内皮细胞中的关键作用，使用小鼠敲除和人类 脑内皮细胞我们将检验有害的THSD 1变体损害 通过干扰局部粘连导致信号失调的内皮细胞功能 通过黏着斑激酶（FAK）介导。这一假设得到了我们初步的支持。 数据包括THSD 1人脑微血管的无偏全局途径分析 内皮敲低细胞。我们预计这项研究将部分阐明 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影响， 从而降低发病率和死亡率。这项工作也有更广泛的意义，在血管 新出现的证据表明Thsd1在内皮屏障功能和保护 动脉粥样硬化和出血性病变的血管系统。

项目成果

Integrated Stroke System Model Expands Availability of Endovascular Therapy While Maintaining Quality Outcomes.

• DOI: 10.1161/strokeaha.120.032710
• 发表时间: 2021-03
• 期刊: Stroke
• 影响因子: 8.3
• 作者: Lopez-Rivera V;Salazar-Marioni S;Abdelkhaleq R;Savitz SI;Czap AL;Alderazi YJ;Chen PR;Grotta JC;Blackburn SL;Jones W;Spiegel G;Dannenbaum MJ;Wu TC;Cochran J;Kim DH;Day AL;Farquhar G;McCullough LD;Sheth SA
• 通讯作者: Sheth SA

Podosome formation impairs endothelial barrier function by sequestering zonula occludens proteins.

足体形成通过隔离闭锁带蛋白损害内皮屏障功能。

• DOI: 10.1002/jcp.29343
• 发表时间: 2020
• 期刊: Journal of cellular physiology
• 影响因子: 5.6
• 作者: Rui,Yan-Ning;Chen,Yawen;Guo,Yichen;Bock,CarolineE;Hagan,JohnP;Kim,DongH;Xu,Zhen
• 通讯作者: Xu,Zhen