Endothelial cell dysfunction in cerebral aneurysm pathogenesis

脑动脉瘤发病机制中的内皮细胞功能障碍

• 批准号: 10529287
• 负责人: Robert Michael Starke
• 金额: $ 50.94万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10529287
• 关键词: Alpha Interleukin 2 Receptor; Aneurysm; Angiography; Anti-Inflammatory Agents; B-Lymphocytes; Berry Aneurysm; Blood; Blood Vessels; Catheters; Cell Proliferation; Cell physiology; Cerebral Aneurysm; Cerebrum; Clinical Research; Data; Development; Devices; Endothelial Cells; Endothelium; Event; FRAP1 gene; Failure; Film; Functional disorder; Gene Expression; Genes; Global Change; Grant; Growth; Human; IL2 gene; Inflammation; Inflammatory; Interdisciplinary Study; Interleukin 2 Receptor; Interleukin-2; Intervention; Knockout Mice; Lead; Ligation; Link; Macrophage; Magnetic Resonance Imaging; Maintenance; Mediating; Mediator; Medical; Microsurgery; Modeling; Molecular; Molecular Analysis; Morbidity - disease rate; Mus; Nanoporous; Neck; Operative Surgical Procedures; Optical Coherence Tomography; Oral; Oryctolagus cuniculus; Oxidative Stress; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Population; Prevention; Process; Proliferating; Quantitative Reverse Transcriptase PCR; Recurrence; Regulation; Research; Retreatment; Risk; Risk Factors; Role; Rupture; Ruptured Aneurysm; Signal Transduction; Sirolimus; Stents; Surgical Clips; T-Lymphocyte; Technology; Testing; Therapeutic; Thinness; Tissues; Transgenic Mice; Treatment Failure; Up-Regulation; Vascular Diseases; Vasomotor; atherosclerosis risk; brain endothelial cell; controlled release; cytokine; endothelial dysfunction; experimental study; healing; imaging modality; in vivo Model; in vivo imaging; inhibitor; innovation; mTOR Inhibitor; mTOR Signaling Pathway; mTOR inhibition; mTOR protein; minimally invasive; mortality; mouse model; novel; pharmacologic; repaired; vascular abnormality; vascular injury

Project Summary/Abstract: Endothelial dysfunction is highlighted as an early marker of vascular abnormality preceding cerebral aneurysm formation, but the molecular events behind this transformation remain unclear. Inflammatory cytokines including interleukin-2 (IL-2) mediate vascular disease, but its role in cerebral aneurysm pathophysiology is unknown. Our preliminary data indicate that IL-2 is expressed in human cerebral aneurysm tissue and induces a phenotypic switch in endothelial cell (EC) function from the maintenance of vasomotor activity, to promotion of inflammation and matrix remodeling. We have also found that inhibition of the IL-2 target protein mTOR with rapamycin reduced aneurysm progression and rupture in a mouse cerebral aneurysm model. Collectively this preliminary data suggests a vital role of the IL-2/mTOR pathway in aneurysm progression. The objective of this grant is to characterize the role of IL-2 activated mTOR in EC dysfunction and aneurysm development and progression. The central hypothesis of this proposal is that IL-2/mTOR inhibition promotes repopulation of EC and decreases inflammation, which halts aneurysm progression and promotes vascular healing. In this proposal, we will determine the role of IL-2 activated mTOR in aneurysm formation, progression, and rupture and define the mechanisms by which IL-2/mTOR promotes EC dysfunction (Aim 1). We will treat experimental aneurysms with a novel stent delivering controlled release of the IL-2/mTOR inhibitor rapamycin to determine if IL-2/mTOR inhibition reverses EC dysfunction while decreasing inflammation (Aim 2). Finally, we will determine IL-2 expression, mTOR activation and EC dysfunction in human cerebral aneurysmal tissue and intra-aneurysmal blood and if rapamycin treatment prior to surgery reduces IL-2/mTOR signaling and EC dysfunction (Aim 3). The proposed research is innovative in that successful completion of this project will determine the events behind EC dysfunction which lead to aneurysm progression and will help develop novel minimally invasive therapeutic strategies for aneurysm obliteration.

项目概要/摘要： 内皮功能障碍是血管异常的早期标志， 脑动脉瘤形成，但这种转变背后的分子事件仍然存在 不清楚包括白细胞介素-2（IL-2）在内的炎性细胞因子介导血管疾病，但其 在脑动脉瘤病理生理学中的作用尚不清楚。我们的初步数据表明，IL-2是 在人脑动脉瘤组织中表达并诱导内皮细胞表型转换 细胞（EC）的功能从维持血管活性，到促进炎症， 基质重塑我们还发现，IL-2靶蛋白mTOR的抑制与IL-2受体的表达有关。 雷帕霉素减少小鼠脑动脉瘤模型中的动脉瘤进展和破裂。 总的来说，这些初步数据表明IL-2/mTOR通路在动脉瘤中起着至关重要的作用。 进展本研究的目的是研究IL-2激活的mTOR在EC中的作用。 功能障碍和动脉瘤的发展和进展。这个问题的核心假设是 建议IL-2/mTOR抑制促进EC再增殖并减少炎症， 从而阻止动脉瘤的发展并促进血管愈合。在本提案中，我们将 确定IL-2激活的mTOR在动脉瘤形成、进展和破裂中的作用， 确定IL-2/mTOR促进EC功能障碍的机制（目的1）。本公司对待 使用新型支架输送IL-2/mTOR控释的实验性动脉瘤 抑制剂雷帕霉素，以确定IL-2/mTOR抑制是否逆转EC功能障碍， 减少炎症（目标2）。最后，我们将确定IL-2表达，mTOR激活， 和EC功能障碍，如果 手术前雷帕霉素治疗减少了IL-2/mTOR信号传导和EC功能障碍（目的3）。 拟议的研究是创新的，成功完成这一项目将决定 EC功能障碍背后的事件导致动脉瘤进展，并将有助于发展 动脉瘤闭塞的新型微创治疗策略。