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 项目概要 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靶点 4.用于预防颅内动脉瘤（IAs）破裂。血流动力学压力异常，例如 5 高壁剪切的冲击流和低壁剪切的振荡流，与生长密切相关 6、IAs破裂。然而，弱 IA 墙背后的详细机制尚未定义，因为 (1) 7 缺乏分析内皮细胞 (EC) 基因表达空间分布的技术 8 由 IAs 中产生的复杂血流动力学压力源引起，(2) 收集连续临床图像的困难 9 培养 IAs 并获取人类 IA 组织样本以验证生物学机制，以及 (3) 缺乏 10 种技术允许集成 3D 多模态技术的数据。为了克服这些障碍，我们 11 建立了一支强大的多学科团队，并创建了一个连接人类样本的新实验系统， 12 个成像和动态建模平台。在这个项目中，我们挑战两个基本问题： 13 IAs 内的血流动力学应激和诱导反应。一、复杂异常的血流动力学应激 14 人类内部的IAs会诱导EC信号通路的异常调节吗？二、信号通路有哪些 15 EC 连接在 IA 生长和破裂过程中不稳定的壁重塑？为了解决这些问题，我们开创了 16 3D 实时 EC 动脉瘤血流模拟器 (3D LEAFS)，用于分析 EC 响应的空间分布 17 患者特定 IAs 中产生的复杂血流动力学流动应力。初步研究表明，异常 IAs 中的 18 流动会导致 EC 形态异常、细胞功能障碍和炎症以及通透性增加。 19 我们开发了一个广泛的数据库，其中包含正在生长的 IAs 和组织样本的临床图像，利用 使用显微 CT 和多光子扫描的人体 IA 组织的 20 个集成血流分析和 3D 组织学成像 21 显微镜检查。通过这个数据库，我们将异常流动与 IAs 与生长、壁变薄和薄弱壁联系起来 22 改造导致破裂。通过结合这些最先进的技术，我们建议研究 23 异常流动应力对 EC 的根本影响，并确定 EC 病理生理学之间的关系 24 反应和壁变化导致壁脆弱、生长和破裂。所提出的研究具有创新性 25 因为这将是第一个利用多模态来回答上述问题的研究，包括 26 个纵向随访图像、手术视频、显微 CT、多光子显微镜、体外 3D 内皮血流 27 模拟器和流量分析，用于开发将流量引起的 EC 反应与病理联系起来的管道 28 人类 IA 组织的变化。该项目的具体目标是：1）确定EC信号通路 29 与不稳定的壁重塑相关，2) 将病理性 EC 反应与 IA 生长相关，以及 3) 30 确定了由几种特征性异常血流动力学条件引起的 EC 反应。这 31 项拟议研究将促进利用诊断成像的精准医学策略的发展 32 具有风险预测和转化疗法。