Inflammatory Mediators and Mechanisms of Cerebral Aneurysm Formation and Rupture

脑动脉瘤形成和破裂的炎症介质和机制

• 批准号: 10393517
• 负责人: Brian Lim Hoh
• 金额: $ 35.39万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10393517
• 关键词: Affect; Aneurysm; Antibodies; Biological Assay; Biology; Blood Vessels; Bone Marrow; CXCL1 gene; Cells; Cephalic; Cerebral Aneurysm; Coculture Techniques; Craniotomy; Data; Development; Devices; Endothelial Cells; Estrogens; Female; Functional disorder; Goals; Growth; Human; IL8RB gene; In Vitro; Inflammation Mediators; Inflammatory Response; Interleukin-17; Knowledge; Laboratory Study; Ligands; Link; Measures; Mediating; Mediator of activation protein; Mission; Modeling; Mus; Neutrophil Infiltration; Operative Surgical Procedures; Outcome; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Population; Public Health; Research; Research Personnel; Retreatment; Role; Rupture; Ruptured Aneurysm; Signal Transduction; Site; Smooth Muscle Myocytes; Stents; Study models; Subarachnoid Hemorrhage; Testing; Tissues; Translating; United States National Institutes of Health; Vascular Cell Adhesion Molecule-1; Work; antagonist; chemokine; cytokine; disability; healing; improved; innovation; macrophage; mortality; mouse model; neutrophil; novel; novel therapeutics; prevent; prophylactic; receptor; therapeutic target

PROJECT SUMMARY/ABSTRACT Cerebral aneurysms affect up to 5% of the population. When cerebral aneurysms rupture, they cause devastating subarachnoid hemorrhage with greater than 50% mortality. Currently, the only treatments that prevent rupture are prophylactic cranial or endovascular surgery which are risky. A gap in knowledge persists about the pathophysiology of aneurysm formation, growth, and rupture. The long-term goal is to improve understanding of the mediators and mechanisms of cerebral aneurysm formation and rupture, and thereby identify therapeutic targets for the development of novel therapies. Our laboratory studies this problem from two different approaches: 1) improve aneurysm endovascular devices to achieve complete aneurysm healing, and 2) improve our understanding of what causes aneurysms to develop and grow. We recently found chemokine (C-X-C motif) ligand 1 (CXCL1) antagonism achieves both: we found CXCL1 antagonism significantly inhibits mouse cerebral aneurysm formation (13.3 versus 66.7%; P =0.0078), and in mouse carotid aneurysms treated with coiling, CXCL1 antagonism, significantly improves intrasaccular aneurysm coil occlusion and healing (preliminary data). Improving our understanding of the mechanisms is intriguing because this could translate to treating patients' aneurysms with coiling, and supplementing with a drug that facilitates intrasaccular aneurysm healing and by a separate mechanism inhibits further cerebral aneurysm growth. Our central hypothesis: CXCL1 antagonism promotes intrasaccular aneurysm occlusion and healing with coiling and protects against cerebral aneurysm formation by modulating the macrophage and neutrophil-mediated site-specific inflammatory response. We will test our central hypothesis with the following aims in this Early Established Investigator application: 1) Demonstrate CXCL1 is necessary for aneurysm rupture. CXCL1 antagonism improves aneurysm healing; 2) Demonstrate IL17 induces CXCL1-mediated aneurysm formation and rupture and CXCL1 inhibition of aneurysm coil healing; and 3) Demonstrate infiltrating macrophages and neutrophils mediate CXCL1-induced aneurysm formation and rupture and CXCL1 inhibition of aneurysm coil healing. The proposal is conceptually innovative in that we will propose a novel link between IL17, CXCL1, neutrophils and macrophages and precisely define their roles as mediators in cerebral aneurysm formation and rupture. Furthermore, the proposed studies are the first to investigate a mediator that both promotes intrasaccular aneurysm healing and protects against cerebral aneurysm growth and rupture. The significance of this work is the potential identification of novel targets with direct translational benefit.

项目总结/摘要 脑动脉瘤影响高达5%的人口。当脑动脉瘤破裂时， 毁灭性的蛛网膜下腔出血死亡率超过50%目前，唯一的治疗， 预防破裂是预防性的颅骨或血管内手术，这是有风险的。知识差距依然存在 关于动脉瘤形成、生长和破裂的病理生理学。长期目标是改善 了解脑动脉瘤形成和破裂的介质和机制，从而 为开发新疗法确定治疗靶点。我们的实验室研究这个问题， 两种不同的方法：1）改进动脉瘤血管内装置以实现完全的动脉瘤愈合， 2）提高我们对动脉瘤发展和生长原因的理解。我们最近发现 趋化因子（C-X-C基序）配体1（CXCL 1）拮抗作用实现了这两个：我们发现CXCL 1拮抗作用 显著抑制小鼠脑动脉瘤形成（13.3%对66.7%; P =0.0078）， 使用弹簧圈栓塞治疗的动脉瘤，CXCL 1拮抗剂，显著改善了囊内动脉瘤弹簧圈栓塞 闭塞和愈合（初步数据）。提高我们对机制的理解是有趣的，因为 这可以转化为用弹簧圈治疗患者的动脉瘤，并补充一种药物， 囊内动脉瘤愈合并通过单独的机制抑制脑动脉瘤的进一步生长。我们 中心假设：CXCL 1拮抗作用促进囊内动脉瘤闭塞和弹簧圈栓塞愈合 并通过调节巨噬细胞和巨噬细胞介导的 部位特异性炎症反应。我们将测试我们的中心假设与以下目标在这早期 确定的研究者应用：1）证明CXCL 1是动脉瘤破裂所必需的。CXCL1 拮抗作用改善动脉瘤愈合; 2）证明IL 17诱导CXCL 1介导的动脉瘤形成 和破裂以及CXCL 1抑制动脉瘤弹簧圈愈合;以及3）显示浸润性巨噬细胞和 中性粒细胞介导CXCL 1诱导的动脉瘤形成和破裂以及CXCL 1对动脉瘤弹簧圈的抑制 治愈该提议在概念上是创新的，因为我们将提出IL 17，CXCL 1， 中性粒细胞和巨噬细胞，并精确定义其作为脑动脉瘤形成介质的作用， 破裂此外，拟议的研究是第一次调查一个调解人，既促进 囊内动脉瘤愈合和防止脑动脉瘤生长和破裂。意义 这项工作的一个重要方面是鉴定具有直接翻译益处的新靶点。