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

基本信息

批准号：
9885597
负责人：
Robert Michael Starke
金额：
$ 42.56万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
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：
2019-12-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9885597
关键词：
Aneurysm Angiography Anti-Inflammatory Agents B-Lymphocytes Berry Aneurysm Blood Blood Vessels Cell Proliferation Cell physiology Cerebral Aneurysm Cerebrum Clinical Research Clip 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 Magnetic Resonance Imaging Maintenance Mediating Mediator of activation protein Medical 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 Pharmacology Phenotype Prevention Process Quantitative Reverse Transcriptase PCR Regulation Research Retreatment Risk Risk Factors Role Rupture Ruptured Aneurysm Signal Transduction Sirolimus Stents 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/antagonist innovation mTOR Inhibitor mTOR Signaling Pathway mTOR inhibition mTOR protein macrophage minimally invasive mortality mouse model novel repaired vascular abnormality vascular injury

项目摘要

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.

项目摘要/摘要：内皮功能障碍被突出显示为先前血管异常的早期标记脑动脉瘤形成，但这种转化背后的分子事件仍然存在不清楚。包括白介素2（IL-2）在内的炎性细胞因子介导了血管疾病，但它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，并诱导内皮中的表型转换细胞（EC）的功能从血管舒缩活性的维持，促进炎症和矩阵重塑。我们还发现，抑制IL-2靶蛋白MTOR 雷帕霉素降低了小鼠脑动脉瘤模型中的动脉瘤进展和破裂。总体而言，此初步数据表明IL-2/mTOR途径在动脉瘤中起着至关重要的作用进展。该赠款的目的是表征IL-2激活MTOR在EC中的作用功能障碍和动脉瘤的发育和进展。中心假设建议是IL-2/mTOR抑制促进EC的重生并减少炎症，阻止动脉瘤进展并促进血管愈合。在此提案中，我们将确定IL-2激活MTOR在动脉瘤形成，进展和破裂中的作用，定义IL-2/mTOR促进EC功能障碍的机制（AIM 1）。我们将对待实验性动脉瘤具有新型支架，可提供IL-2/mTOR的受控释放抑制剂雷帕霉素确定IL-2/mTOR抑制是否会逆转EC功能障碍，而减少炎症（AIM 2）。最后，我们将确定IL-2表达，mTOR激活和EC功能障碍在人脑动脉瘤组织和炎性瘤血液中的功能障碍，以及手术前的雷帕霉素治疗可降低IL-2/mTOR信号传导和EC功能障碍（AIM 3）。拟议的研究具有创新性，因为该项目的成功完成将决定 EC功能障碍导致动脉瘤进展的事件，并将有助于发展新颖的动脉瘤抑制作用微创治疗策略。