Bridging the Gap from Hemodynamic Stress to Intracranial Aneurysm Instability: An Integrated Multimodal Approach

弥合血流动力学应激与颅内动脉瘤不稳定之间的差距：综合多模式方法

• 批准号: 10610461
• 负责人: Naoki Kaneko
• 金额: $ 48.94万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10610461
• 关键词: 3-Dimensional; 3D Print; Abnormal Endothelial Cell; Address; Affect; Aneurysm; Angiography; Animal Model; Area; Biological; Biological Markers; Bulla; Cell Shape; Cellular Morphology; Characteristics; Clinical; Collaborations; Complex; Data; Data Set; Databases; Development; Diagnostic Imaging; Endothelial Cells; Endothelium; Exhibits; Functional disorder; Gene Expression; Goals; Growth; Harvest; Human; Image; In Vitro; Inflammation; Intracranial Aneurysm; Investigation; Knowledge; Link; Liquid substance; Maps; Mediating; Medical; Methods; Microscopic; Microscopy; Microsurgery; Modeling; Molecular; Monitor; Morbidity - disease rate; Operative Surgical Procedures; Pathologic; Patients; Permeability; Pharmacotherapy; Prevention; Regulation; Reporting; Research; Risk; Risk Factors; Role; Rupture; Ruptured Aneurysm; Sampling; Scanning; Signal Pathway; Signal Transduction; Source; Spatial Distribution; Specific qualifier value; Stress; Subarachnoid Hemorrhage; Surgical Clips; System; Techniques; Technology; Testing; Thinness; Time; Tissue Sample; Tissues; Unnecessary Surgery; Vascular Endothelial Cell; cerebrovascular; clinical database; clinical imaging; data integration; follow-up; hemodynamics; high risk; histological image; human imaging; in vitro Model; innovation; microCT; mortality; multi-photon; multidisciplinary; multimodality; multiphoton microscopy; novel; pharmacologic; precision medicine; predictive tools; radiological imaging; response; risk prediction; simulation; stressor; translational therapeutics

1 Project Summary 2 3 The overall goal of this project is to develop accurate and reliable prediction tools and pharmacological targets 4 for the prevention of rupture of intracranial aneurysms (IAs). Abnormal hemodynamic stress such as 5 impingement flow with high wall shear and oscillating flow with low wall shear, is intimately linked with the growth 6 and rupture of IAs. However, detailed mechanisms underlying weak IA walls are not yet defined due to (1) the 7 absence of technologies for profiling the spatial distribution of gene expression of endothelial cells (ECs) induced 8 by the complex hemodynamic flow stressors created in IAs, (2) difficulties in collecting sequential clinical images 9 of growing IAs and acquiring human IA tissue samples to validate biologic mechanisms, and (3) the absence of 10 technologies allowing integration of the data from 3D multimodal techniques. To overcome these obstacles, we 11 have built a strong, multidisciplinary team and created a new experimental system that bridges human samples, 12 imaging, and dynamic modeling platforms. In this project, we challenge two fundamental questions regarding 13 hemodynamic stress and induced responses within the IAs. First, does complex abnormal hemodynamic stress 14 within human IAs induce abnormal regulation of EC signaling pathways? Second, what signaling pathways in 15 EC link unstable wall remodeling during IA growth and rupture? To address these questions, we have pioneered 16 a 3D Live EC Aneurysmal Flow Simulator (3D LEAFS) for profiling the spatial distribution of EC responses to 17 complex hemodynamic flow stress created in patient-specific IAs. Preliminary studies demonstrate that abnormal 18 flow in IAs induces abnormal EC morphology, cellular dysfunction and inflammation, and increased permeability. 19 We have developed an extensive database of clinical images of growing IAs and also tissue samples, exploiting 20 integrated flow analysis and 3D histological imaging of human IA tissue scanned with micro-CT and multiphoton 21 microscopy. With this database, we have linked abnormal flow with IAs to growth, wall thinning and weak wall 22 remodeling leading to rupture. By combining these state-of-the-art technologies, we propose to examine 23 fundamental impact of abnormal flow stress on ECs, and identify relationships between EC pathophysiological 24 responses and wall changes leading to fragile walls, growth and rupture. The proposed research is innovative 25 because this will be the first research to answer the above questions by utilizing multimodalities including 26 longitudinal follow-up images, surgical video, micro-CT, multiphoton microscopy, in vitro 3D endothelialized flow 27 simulator, and flow analysis for development of a pipeline for linking flow-induced EC responses to pathologic 28 changes in human IA tissue. The specific aims of this project are: 1) determine the EC signaling pathways 29 associated with unstable wall remodeling, 2) correlate pathological EC responses with IA growth, and 3) 30 determine the EC responses evoked by several characteristic abnormal hemodynamic flow conditions. The 31 proposed research will enhance development of precision medicine strategies that leverage diagnostic imaging 32 with risk prediction and translational therapies.

1个项目摘要 2 3该项目的总体目标是开发准确可靠的预测工具和药理学目标 4用于预防颅内动脉瘤破裂（IAS）。异常血液动力学应激，例如 5高壁剪切和低壁剪切振荡流的撞击流与生长密切相关 6和IAS破裂。但是，由于（1） 7缺乏用于培养内皮细胞基因表达（EC）的空间分布的技术 8由IAS产生的复杂血流动力流动应力源，（2）收集顺序临床图像的困难 9个生长的IAS和获取人IA组织样品以验证生物学机制，以及（3）不存在 10个允许从3D多模式技术集成数据的技术。为了克服这些障碍，我们 11建立了一个强大的多学科团队，并创建了一个新的实验系统，该系统桥接了人类样本， 12个成像和动态建模平台。在这个项目中，我们挑战了两个有关的基本问题 13 IAS内血流动力学应力和诱导的反应。首先，要进行复杂的异常血流动力应激 14在人类IAS中诱导EC信号通路的异常调节？第二，什么信号通路 15 EC在IA生长和破裂过程中链接不稳定的壁重塑？为了解决这些问题，我们已经开创了 16 A 3D Live EC动脉瘤流量模拟器（3D LEAFS），用于分析EC响应的空间分布 17在患者特异性IAS中产生的复杂血流动力学应力。初步研究表明异常 18 IAS的流动引起异常的EC形态，细胞功能障碍和炎症，并增加渗透率。 19我们开发了一个广泛的IAS临床图像的数据库，还开发了组织样品 20用Micro-CT和多光子扫描的人IA组织的综合流动分析和3D组织学成像 21显微镜。使用此数据库，我们将异常流与IAS连接到生长，壁变薄和弱壁 22重塑导致破裂。通过结合这些最先进的技术，我们建议检查 23异常流动应力对EC的基本影响，并确定EC病理生理学之间的关系 24个反应和壁变化，导致墙壁脆弱，生长和破裂。拟议的研究是创新的 25，因为这将是第一个通过利用包括多模式在内的上述问题的研究 26个纵向后续图像，手术视频，微CT，多光子显微镜，体外3D内皮化流动 27模拟器和用于开发管道的流量分析，用于将流动诱导的EC响应与病理联系起来 28人IA组织的变化。该项目的具体目的是：1）确定EC信号通路 29与不稳定的壁重塑相关，2）将病理EC的反应与IA的增长相关，3） 30确定了几种特征异常血流动力学流动条件引起的EC反应。这 31拟议的研究将增强利用诊断成像的精确医学策略的发展 32具有风险预测和转化疗法。