RUI: Probing the Mechanotransduction of Disturbed Flow in Brain Vasculature

RUI：探讨脑脉管系统扰动流的机械转导

基本信息

批准号：
1728239
负责人：
Peter Galie
金额：
$ 29.89万
依托单位：
Rowan University
依托单位国家：
美国
项目类别：
Standard Grant
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2021-08-31
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=1728239&HistoricalAwards=false
关键词：
RUI Probing Mechanotransduction Disturbed Flow

项目摘要

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.

头部血管中的动脉瘤对普通人群构成了重大健康风险。绝大多数大脑动脉瘤在分支点和动脉连接处形成，其中血流被其流动路径突然变化“干扰”。受干扰的血流改变了施加在脑动脉内部细胞上的机械力，尽管这些力对动脉瘤形成的贡献尚不完全清楚。确定流动诱导的力对活大脑内部细胞的影响很困难，因此需要开发模型的血管系统，以重现生活中发生的事情。该模型必须模仿独特的“血脑屏障”，以改变脑脉管系统与身体其他部位相比的工作方式。该研究将使用这种模型来确定流动障碍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的影响，并提出可能阻止处于危险患者的动脉瘤形成的分子靶标。这项研究将培训本科生和研究生进行实验室工作。来自新泽西州卡姆登市的高中生将被招募在实验室工作。该赠款将增加罗恩大学在新泽西州南部建立研究计划的努力。该项目的总体目标是确定脑内皮细胞对流体流动的生物学反应，并研究该反应的分子机制。寒冷动脉瘤和动脉分叉之间的空间相关性令人震惊，这使公认的观点借鉴了可接受的观点，即扰乱分叉部位流动的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。微粒图像速度法与计算流体动力学结合使用，以表征该模型内皮上施加的剪切应力曲线。响应于施加的流体流动方案，将测量由内皮细胞的基因重塑标记的基因和蛋白质表达。研究将检验以下假设：CD44及其下游效应子在脑脉管系统中起干扰流动的机械传感器。中心假设是，流动介导的CD44激活导致紧密的连接破坏和基质金属蛋白酶通过RhoA GTPase激活。识别负责转导干扰流动的机制，不仅可以提高对细胞如何反应机械力的基本理解，而且还阐明了为什么颅内动脉瘤形成了为什么在动脉分叉附近形成。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Hyaluronan Disrupts Cardiomyocyte Organization within 3D Fibrin-Based Hydrogels

DOI：
10.1016/j.bpj.2019.02.018
发表时间：
2019-04-02
期刊：
BIOPHYSICAL JOURNAL
影响因子：
3.4
作者：
Bouhrira, Nesrine;Galie, Peter A.;Janmey, Paul A.
通讯作者：
Janmey, Paul A.

Multivascular networks and functional intravascular topologies within biocompatible hydrogels.

DOI：
10.1126/science.aav9750
发表时间：
2019-05-03
期刊：
Science (New York, N.Y.)
影响因子：
0
作者：
Grigoryan B;Paulsen SJ;Corbett DC;Sazer DW;Fortin CL;Zaita AJ;Greenfield PT;Calafat NJ;Gounley JP;Ta AH;Johansson F;Randles A;Rosenkrantz JE;Louis-Rosenberg JD;Galie PA;Stevens KR;Miller JS
通讯作者：
Miller JS

Disturbed flow disrupts the blood-brain barrier in a 3D bifurcation model