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

基本信息

批准号：
9543032
负责人：
Dong H Kim
金额：
$ 33.69万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9543032
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 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

项目摘要

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）。尽管有治疗进步，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，大约发生了大约30,000个SAH案件每年。在破裂之前，IAS通常是无症状的，通常不会引起注意。什么时候在破裂前确定和治疗，生存率显着提高。因此，早检测，适当的监测和及时对IAS的治疗至关重要防止残疾和过早死亡。我们的研究小组最近牵涉到稀有变体在血小板素型1中，含域的蛋白1（THSD1）在家族性和零星IA中均和SAH病例使用人类遗传学和动物模型。 THSD1的特征很差其表达在很大程度上仅限于内皮细胞的基因。在这里，我们试图阐明 THSD1在脑血管内皮细胞中的关键作用，同时使用小鼠敲除和人脑内皮细胞。我们将测试有害THSD1变体损害的假设内皮细胞功能通过扰动局灶性粘附，导致信号失调通过局灶性粘附激酶（FAK）介导。这个假设得到了我们的初步支持数据包括对THSD1人脑微血管的无偏全球途径分析内皮敲低细胞。我们预计这项研究将部分阐明基础导致IA形成和破裂的机制。此外，将有新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。这项工作在血管中也具有更广泛的影响生物学作为新兴证据牵涉到内皮屏障功能和保护中的THSD1 动脉粥样硬化和出血性病变中的脉管系统。