Functional Validation of Intracranial Aneurysm Risk Genes

颅内动脉瘤风险基因的功能验证

• 批准号: 10093164
• 负责人: MURAT GUNEL
• 金额: $ 60.6万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10093164
• 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; Fatal Outcome; Focal Adhesions; Functional disorder; Future; G-Protein-Coupled Receptors; GTP-Binding Protein alpha Subunits, Gs; Gene Dosage; Gene Expression; Genes; Genetic; Genetic Transcription; Genetic Variation; Genetic study; Genomics; Health; 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; PF4 Gene; 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; 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; mortality; mouse model; prognostic; response; risk variant; shear stress; src-Family Kinases; targeted treatment; three dimensional structure; vascular abnormality; vasoconstriction

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.

在美国和全世界，颅内动脉瘤(IA)是一个重要的健康问题。它们的破裂导致了 颅内出血，具有毁灭性的后果：30%的IA破裂患者在手术后一个月内死亡 在最初的事件中，50%的幸存者留下了严重的神经缺陷，需要长期护理。在我们的 在之前的研究中，我们完成了一系列全基因组关联研究(GWAS)，其中确定了几个 包含候选IA风险基因的IA风险基因座。我们现在建议研究SELECT基因的生物学意义 在人血管内皮细胞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 在斑马鱼和老鼠身上的这些发现是理想的遗传操作和 脑血管系统的分析。拟议中的研究将建立基因调控的机制 剂量可能会增加动脉瘤形成的风险，这验证了它们影响血管的假设 动态平衡与血管张力调节如果成功，这些研究将刺激未来对理性的研究 以及治疗IA的分子信息治疗方法。