RUI: Probing the Mechanotransduction of Disturbed Flow in Brain Vasculature

头部血管中的动脉瘤对一般人群构成重大健康风险。绝大多数的脑动脉瘤形成于动脉的分支点和连接处，在那里，血流被其流动路径的突然变化“干扰”。干扰的血流改变了施加在脑动脉内衬细胞上的机械力，尽管这些力对动脉瘤形成的贡献还不完全清楚。确定流动诱导力对活脑内细胞的影响是困难的，需要开发模型血管系统来再现生活中发生的事情。这个模型必须模仿独特的“血脑屏障”，与身体其他部位的血管相比，血脑屏障改变了大脑血管系统的工作方式。 该研究将使用这样的模型来确定扰动流对与动脉瘤形成相关的细胞过程的影响。该项目将更好地了解大脑中血流紊乱的影响，并提出可能预防高危患者动脉瘤形成的分子靶点。这项研究将训练本科生和研究生进行实验室工作。来自新泽西州卡姆登的高中生将被招募到实验室工作。 这笔赠款将增加罗文大学在新泽西南部建立一个研究项目的努力。本项目的总体目标是确定脑内皮细胞对扰动流体流动的生物学反应，并研究这种反应的分子机制。囊状动脉瘤和动脉分叉之间的空间相关性是惊人的，这证实了公认的观点，即分叉部位的扰动流动有助于动脉瘤的形成和进展。这些研究依赖于脑动脉分叉的三维体外模型。 微粒图像测速结合计算流体动力学来表征该模型内施加在内皮上的剪切应力分布。将测量响应于所施加的流体流动方案的内皮细胞的基质重塑标志物的基因和蛋白质表达。研究将检验cd44及其下游效应物作为脑血管中扰动血流的机械传感器的假设。中心假设是，干扰的流动介导的活化的CD44的结果在紧密连接破坏和基质金属蛋白酶的激活，通过RhoA GTdR。识别负责转导干扰流的机制不仅推进了对细胞如何响应机械力的基本理解，而且还澄清了为什么颅内动脉瘤在动脉分叉附近形成。

Aneurysms in blood vessels of the head pose a substantial health risk to the general population. The vast majority of brain aneurysms form at branch points and junctions of arteries, where blood flow is 'disturbed' by sudden changes in its flow path. Disturbed blood flow alters the mechanical force exerted on cells lining cerebral arteries, though the contribution of these forces to aneurysm formation is not fully known. Determining the effect of flow-induced forces on cells inside a living brain is difficult, necessitating the development of model vascular systems that reproduce what happens in life. This model must mimic the unique the 'blood-brain barrier' that changes how the brain vasculature works compared to vessels in the rest of the body. The research will use such a model to determine the effect of disturbed flow on cellular processes associated with aneurysm formation. The project will yield a better understanding of the effects of disturbed blood flow in the brain, and suggest molecular targets that may prevent aneurysm formation in at-risk patients. The research will train undergraduates and graduate students to perform laboratory work. High school students from Camden, NJ will be recruited to work in the laboratory. The grant will add to Rowan University's effort to build a research program in southern New Jersey. The overall goal of this project is to determine the biological response of cerebral endothelial cells to disturbed fluid flow and to investigate the molecular mechanisms underlying this response. The spatial correlation between saccular aneurysms and arterial bifurcations is striking, lending credence to the accepted view that disturbed flow at the sites of bifurcation contributes to the formation and progression of aneurysms. These studies rely on a three-dimensional, in vitro model of a cerebral artery bifurcation. Microparticle image velocimetry is used in combination with computational fluid dynamics to characterize the shear stress profiles exerted on the endothelium within this model. Gene and protein expression of matrix remodeling markers by endothelial cells will be measured in response to the applied fluid flow regimes. Studies will test the hypothesis that cd44 and its downstream effectors function as a mechanosensor of disturbed flow in cerebral vasculature. The central hypothesis is that disturbed flow-mediated activation of CD44 results in tight junction disruption and matrix metalloproteinase activation through RhoA GTPase. Identification of the mechanism responsible for transducing disturbed flow not only advances the fundamental understanding of how cells respond to mechanical forces, but also clarifies why intracranial aneurysms form in proximity to arterial bifurcations.