Shear Stress and Endothelial Pathophysiology in Intracranial Atherosclerosis

项目摘要/摘要 这项提议的总体目标是确定低剪应力(0-4dyne/cm2)的震源区 紧邻ICAD下游或狭窄后节段的是动脉粥样硬化形成的标志，提供了 抗炎或抗血栓干预的治疗目标。我们的中心假设是后- 狭窄低切应力与致动脉粥样硬化内皮细胞的病理生理相关 ICAD的精准医学。我们关于SAMMPRIS内这些区域低剪应力的初步数据 确认切应力与血管内皮细胞病理生理相关的潜在影响作用 全身性动脉粥样硬化，但首次扩展到脑循环。我们的三个独立的 具体目标利用持续的、宝贵的合作和SAMMPRIS数据无与伦比的质量 存档。加州大学洛杉矶分校的神经血管成像研究中心将进行前瞻性实验 用详细的解剖流动模型验证大脑中动脉ICAD的CTA CFD测量的局部低剪应力 从相同的源图像创建，在4D MRA[SA-1]上测量共同配准的流量。此步骤将启用 美国将使用这些经过验证的流动模型直接观测流动漩涡和相邻的颗粒低剪应力 显微镜下图像测速仪[SA-1]。这些经过验证的MCA流量模型可作为 内皮，可以研究细胞形态、VCAM-1的表达和血小板聚集[SA- 2]。在这50个大脑中动脉病变中，狭窄后低剪应力(0-4dyne/cm2)的临床相关性将是 通过与对侧同源节段[SA-3]的CTA CFD比较得到证实。的协会 这一明确定义的狭窄后低剪应力的潜在治疗靶点将在以下方面进行研究 SAMMPRIS的其他临床变量和随后的神经学结果[SA-3]。这些观察结果 将对所有140名SAMMPRIS CTA CFD受试者进行类似的调查，以调查 其他动脉病变部位的非侵入性CTA CFD[SA-3]。所有图像后处理、CTA CFD、4D MRA、3D 我们将在加州大学洛杉矶分校进行内皮病理生理学的印刷和生物检测，我们在那里有 开创了这一工作流程。Wasid和SAMMPRIS审判领导层的合作和指导是一项 这是ICAD新方法的重要组成部分，它利用了埃默里大学的统计专业知识 具有里程碑意义的试验及其详细的成像和临床分析。我们广泛的前期工作反映了 在新的成像和生物框架方面的协作专业知识，以及密集的经验链接 SAMMPRIS成像和临床数据集提供了关于致动脉粥样硬化LOW知识的合理扩展 切应力进入脑循环。

PROJECT SUMMARY/ABSTRACT The overall goal of this proposal is to establish that the focal region of low shear stress (0-4 dyne/cm2) immediately downstream or in the post-stenotic segment of ICAD is a marker of atherogenesis, providing a therapeutic target for anti-inflammatory or anti-thrombotic interventions. Our central hypothesis is that post- stenotic low shear stress associated with atherogenic endothelial pathophysiology provides a rational basis for precision medicine of ICAD. Our preliminary data on low shear stress in these regions within SAMMPRIS confirm the potential influential role of shear stress associated with endothelial pathophysiology recognized in systemic atherosclerosis, yet extended to the cerebral circulation for the first time. Our three independent specific aims leverage an ongoing, invaluable collaboration and the unmatched quality of the SAMMPRIS data archive. The Neurovascular Imaging Research Core at UCLA will conduct the prospective experiments to validate focal low shear stress measured on CTA CFD of MCA ICAD with detailed anatomical flow models created from the same source images, with co-registered flow measured on 4D MRA [SA-1]. This step enables us to use these validated flow models to directly observe flow vortices and adjacent low shear stress on particle image velocimetry under microscopy [SA-1]. These validated MCA flow models serve as a scaffold for endothelium, where the cell morphology, expression of VCAM-1 and platelet aggregation can be studied [SA- 2]. The clinical relevance of post-stenotic low shear stress (0-4 dyne/cm2) in these 50 MCA lesions will be corroborated via comparison with CTA CFD of the contralateral homologous segment [SA-3]. Associations of this clearly defined potential therapeutic target of post-stenotic low shear stress will be examined with respect to other clinical variables and subsequent neurological outcomes in SAMMPRIS [SA-3]. These observations will be similarly conducted across all 140 SAMMPRIS CTA CFD subjects to investigate the generalizability of non-invasive CTA CFD in other arterial lesion sites [SA-3]. All image post-processing, CTA CFD, 4D MRA, 3D printing and biological assays of endothelial pathophysiology will be conducted at UCLA, where we have pioneered this workflow. The collaboration and guidance of the WASID and SAMMPRIS trial leadership is an important element of this new approach to ICAD that employs the statistical expertise at Emory of these landmark trials and their detailed imaging and clinical analyses. Our extensive preliminary work reflecting collaborative expertise on a novel imaging and biological framework, coupled with intensive experience linking the SAMMPRIS imaging and clinical datasets, provide a logical extension of knowledge on atherogenic low shear stress into the cerebral circulation.