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：
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
项目类别：
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

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) 是脑动脉壁中的一个薄弱区域，会导致异常扩张并可能破裂导致蛛网膜下腔出血（SAH）。尽管接受治疗进展，动脉瘤破裂死亡率超过40%，幸存者仅二分之一返回到独立生活。仅在美国，就有大约 30,000 例 SAH 病例发生每年。在破裂之前，IA 通常是无症状的并且通常不会被注意到。什么时候在破裂前发现并治疗，存活率显着提高。因此，早发现、适当监测和及时治疗 IAs 至关重要防止残疾和过早死亡。我们的研究团队最近发现了罕见的变异家族性和散发性 IA 中血小板反应蛋白 1 型结构域蛋白 1 (THSD1) 使用人类遗传学和动物模型研究 SAH 病例。 THSD1 是一个特征较差的其表达主要限于内皮细胞的基因。在此，我们试图阐明使用小鼠敲除模型和人类模型研究 THSD1 在脑血管内皮细胞中的关键作用脑内皮细胞。我们将检验有害的 THSD1 变异会损害这一假设通过扰乱粘着斑导致信号传导失调来影响内皮细胞功能通过粘着斑激酶（FAK）介导。这个假设得到了我们初步的支持数据包括 THSD1 人脑微血管的无偏全球通路分析内皮敲低细胞。我们预计这项研究将部分阐明潜在的导致 IA 形成和破裂的机制。此外，还会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。这项工作在血管方面也具有更广泛的影响生物学作为新证据表明 Thsd1 与内皮屏障功能和保护有关动脉粥样硬化和出血性病变中的脉管系统。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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：
发表时间：
2020
期刊：
影响因子：
5.6
作者：
Rui, Yan;Chen, Yawen;Guo, Yichen;Bock, Caroline E;Hagan, John P;Kim, Dong H;Xu, Zhen
通讯作者：
Xu, Zhen

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

综合中风系统模型扩大了血管内治疗的可用性，同时保持了高质量的治疗结果。

DOI：
发表时间：
2021
期刊：
影响因子：
8.3
作者：
Lopez;Salazar;Abdelkhaleq, Rania;Savitz, Sean I;Czap, Alexandra L;Alderazi, Yazan J;Chen, Peng R;Grotta, James C;Blackburn, Spiros L;Jones, Wesley;Spiegel, Gary;Dannenbaum, Mark J;Wu, Tzu;Cochran, Joseph
通讯作者：
Cochran, Joseph

Intracranial Aneurysms: Pathology, Genetics, and Molecular Mechanisms.

颅内动脉瘤：病理学、遗传学和分子机制。