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

1项目概要 2 ③本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（IA）破裂。异常血流动力学应激，如 5高壁面剪切的冲击流和低壁面剪切的振荡流与生长密切相关 6和IA的破裂。然而，由于以下原因，导致弱IA壁的详细机制尚未确定：（1） 7.缺乏用于分析诱导的内皮细胞（EC）基因表达的空间分布的技术 8例由颅内动脉内产生的复杂血流动力学压力源引起，（2）难以收集连续的临床图像 9）生长IA和获取人类IA组织样本以验证生物学机制，以及（3）缺乏 10种技术允许从3D多模态技术中整合数据。为了克服这些障碍，我们 11已经建立了一个强大的，多学科的团队，并创建了一个新的实验系统，连接人体样本， 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颅内动脉内的血流动力学应激和诱导反应。首先，复杂的异常血流动力学应激 14在人类IA诱导EC信号通路的异常调节？第二，什么样的信号通路， 15 EC连接IA生长和破裂期间的不稳定壁重塑？为了解决这些问题，我们开创了 16三维实时EC动脉瘤血流模拟器（3D LEAFS），用于分析EC响应的空间分布， 17例患者特定IA中产生的复杂血流动力学流动应力。初步研究表明， IA中的18流动诱导异常EC形态、细胞功能障碍和炎症以及增加的渗透性。 19我们已经开发了一个广泛的临床图像数据库，其中包括正在生长的IA和组织样本， 20用微CT和多光子扫描的人IA组织的集成流动分析和3D组织学成像 21显微镜。利用这个数据库，我们将异常流动与IA与生长、壁变薄和弱壁联系起来 第22章导致死亡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脆弱的壁，生长和破裂。建议的研究是创新的 25因为这将是第一个通过利用多种方式回答上述问题的研究， 26例纵向随访图像、手术视频、显微CT、多光子显微镜、体外3D内皮化血流 27模拟器，和流动分析，用于开发用于将流动诱导的EC反应与病理性EC反应联系起来的管道。 人体IA组织中的28处变化。本课题的具体目标是：1）确定EC信号通路 29例与不稳定的室壁重塑相关，2）病理性EC反应与IA生长相关，以及3） 30确定由几种特征性异常血流动力学流动条件诱发的EC响应。的 31项拟议的研究将促进利用诊断成像的精准医学战略的发展 32例进行了风险预测和转化治疗。

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.