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: 9887928
• 负责人: Brian Lim Hoh
• 金额: $ 37.74万
• 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/9887928
• 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; 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; 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.

项目摘要/摘要 脑动脉瘤影响了高达5%的人口。当脑动脉瘤破裂时，它们会导致 蛛网膜下腔出血致死率超过50%。目前，唯一的治疗方法是 预防破裂的方法是预防性的颅脑或血管内手术，这是有风险的。知识的鸿沟依然存在 关于动脉瘤形成、生长和破裂的病理生理学。长期目标是改进 了解脑动脉瘤形成和破裂的介质和机制，从而 确定用于开发新疗法的治疗目标。我们的实验室从以下方面研究这个问题 两种不同的方法：1)改进动脉瘤血管内装置，以实现动脉瘤的完全愈合， 2)提高我们对动脉瘤发生和增长原因的认识。我们最近发现 趋化因子(C-X-C基序)配体1(CXCL1)拮抗作用达到两者：我们发现CXCL1拮抗作用 显著抑制小鼠脑动脉瘤的形成(13.3%比66.7%；P=0.0078)； CXCL1拮抗剂弹簧圈治疗动脉瘤显著改善囊内动脉瘤弹簧圈 咬合和愈合(初步数据)。提高我们对这些机制的理解很耐人寻味，因为 这可以转化为用弹簧圈治疗患者的动脉瘤，并辅以一种有助于 囊内动脉瘤的愈合和通过一个单独的机制抑制进一步的脑动脉瘤生长。我们的 中心假设：CXCL1拮抗剂促进动脉瘤闭塞和弹簧圈愈合 并通过调节巨噬细胞和中性粒细胞介导的方式预防脑动脉瘤的形成 部位特异性炎症反应。在这个早期阶段，我们将通过以下目标来测试我们的中心假设 已确定的研究人员应用：1)证明CXCL1是动脉瘤破裂所必需的。CXCL1 拮抗作用促进动脉瘤愈合；2)证明IL17诱导CXCL1介导的动脉瘤形成 破裂和CXCL1抑制动脉瘤弹簧圈的愈合；3)显示巨噬细胞和 中性粒细胞介导CXCL1诱导的动脉瘤形成和破裂及CXCL1抑制动脉瘤弹簧圈 治愈。这项建议在概念上是创新的，因为我们将提出IL17、CXCL1、 并准确定义它们在脑动脉瘤形成和发展过程中的中介作用。 破裂。此外，拟议的研究是第一次调查一种既促进 囊腔内动脉瘤的愈合和防止脑动脉瘤的生长和破裂。它的意义 这项工作的一个潜在目标是识别具有直接翻译益处的新靶标。