Functional Validation of Intracranial Aneurysm Risk Genes

颅内动脉瘤风险基因的功能验证

基本信息

批准号：
10552686
负责人：
MURAT GUNEL
金额：
$ 60.58万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10552686
关键词：
Adult Affect Aneurysm Animal Model Architecture BCAR1 gene Bioinformatics Biological Biological Models Biological Process Blood Vessels Blood flow Brain hemorrhage CRISPR/Cas technology Candidate Disease Gene Cell Adhesion Cell Line Cell model Cellular Morphology Cerebrovascular system Complex Cytoskeleton Diagnostic Disease Elements Embryo Endothelial Cells Endothelium Etiology Event Focal Adhesions Functional disorder Future G-Protein-Coupled Receptors Gene Dosage Gene Expression Genes Genetic Genetic Transcription Genetic Variation Genetic study Genomics Health Heterozygote Homeostasis Human Image Intracranial Aneurysm Intracranial Hemorrhages Left Long-Term Care Mediating Meta-Analysis Methods Molecular Molecular Genetics Morbidity - disease rate Morphology Mus Nature Neurologic Deficit Nucleic Acid Regulatory Sequences Orthologous Gene Outcome Pathogenesis Pathway interactions Patients Permeability Phosphorylation Physiology Play Predisposition Public Health Regulation Research Risk Role Rupture Series Signal Transduction Single Nucleotide Polymorphism Map Smooth Muscle Myocytes Stress Stroke Structure Subarachnoid Hemorrhage Survivors Testing Therapeutic Untranslated RNA Validation Vascular Endothelial Cell Vascular Permeabilities Vascular Smooth Muscle Zebrafish candidate identification candidate selection cell motility cell type clinically relevant follow-up genetic analysis genetic approach genetic architecture genetic manipulation genetic risk factor genome editing genome wide association study hemodynamics improved intracranial artery knock-down model organism mortality mouse model prognostication response risk variant shear stress src-Family Kinases targeted treatment three dimensional structure vascular abnormality vasoconstriction

项目摘要

Intracranial aneurysms (IA) represent a significant health issue in the US and worldwide. Their rupture leads to intracranial hemorrhage, with devastating outcomes: 30% of patients with ruptured IA die within a month of the initial event, and 50% of survivors are left with severe neurological deficits requiring long-term care. In our previous studies, we completed a series of genome-wide association studies (GWAS), which identified several IA risk loci containing candidate IA risk genes. We now propose to investigate the biological significance of select candidate genes using genome editing in human endothelial and vascular smooth muscle cell lines, and validate these findings in zebrafish and mouse, two model organisms that are ideal for genetic manipulations and analyses of brain vasculature. The proposed studies will establish the mechanisms by which modulation of gene dosage may enhance risk of aneurysm formation, testing to the hypothesis that they impact vascular homeostasis and vessel tone regulation. If successful, these studies will stimulate future research into rational and molecularly informed therapeutic approaches for IA.

颅内动脉瘤（IA）代表了美国和全球的重大健康问题。他们的破裂导致颅内出血，有毁灭性的结果：30％的IA破裂患者在一个月内死亡最初的事件和50％的幸存者留下了需要长期护理的严重神经缺陷。在我们的先前的研究，我们完成了一系列全基因组关联研究（GWAS），该研究确定了几个 IA风险基因座含有候选IA风险基因。我们现在建议研究选择的生物学意义在人内皮和血管平滑肌细胞系中使用基因组编辑的候选基因，并验证这些发现在斑马鱼和小鼠中，这是两个模型的生物，它们非常适合基因操纵和脑脉管系统的分析。拟议的研究将确定基因调节的机制剂量可能会增加动脉瘤形成的风险，检验它们会影响血管的假设体内平衡和船舶音调调节。如果成功，这些研究将刺激未来对理性的研究并为IA提供了分子知情的治疗方法。