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

1个项目摘要 2. 这个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预防颅内动脉瘤破裂(IAS)。异常血流动力学应激，如 5具有高壁面剪切的撞击流和低壁面剪切的振荡流与生长密切相关。 6和IAS破裂。然而，由于(1)动脉壁薄弱的具体机制尚未明确。 7缺乏分析血管内皮细胞基因表达空间分布的技术 8由于IAS产生的复杂的血流动力学应激源，(2)难以收集连续的临床图像 9.培养IAS并获取人类IA组织样本以验证生物机制，以及(3)缺乏 允许集成来自3D多模式技术的数据的10项技术。为了克服这些障碍，我们 11人建立了一支强大的多学科团队，并创建了一种新的实验系统，将人类样本连接起来， 12个成像、动态建模平台。在这个项目中，我们挑战关于以下两个基本问题 13 IAS内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IAS中诱导EC信号通路的异常调节？第二，在哪些信号通路中 15 EC在动脉粥样硬化生长和破裂过程中是否存在不稳定的室壁重构？为了解决这些问题，我们开创了 16 3D实时EC动脉血流模拟器(3D Leafs)，用于描绘EC响应的空间分布 17在患者特定的IAS中产生复杂的血液动力学流动应力。初步研究表明，异常 IAS中的血流导致EC形态异常、细胞功能障碍和炎症，并增加通透性。 19我们已经开发了一个广泛的数据库，其中包括正在生长的IAS的临床图像以及组织样本，利用 20人颈内动脉组织的微CT和多光子扫描的综合流动分析和三维组织成像 21显微镜。通过这个数据库，我们将IAS的异常流动与生长、壁薄和弱壁联系在一起 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异常流动应力对内皮细胞的基本影响，并确定内皮细胞病理生理之间的关系 24反应和壁变导致壁脆、生长和破裂。建议的研究具有创新性。 因为这将是第一次利用多种模式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内皮化血流 27模拟器和流动分析，用于开发将流动诱导的EC反应与病理联系起来的管道 28人IA组织的变化。本课题的具体目标是：1)确定EC信号转导途径 29与不稳定的室壁重塑有关，2)病理性EC反应与IA生长相关，3) 30确定几种特征性血流异常情况所引起的EC反应。这个 31拟议的研究将加强利用诊断成像的精准医学战略的开发 32风险预测和转化性治疗。

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.