Biophysical Aspects of Leukocyte Transmigration through the Vascular Endothelium

白细胞通过血管内皮迁移的生物物理方面

基本信息

批准号：
8010157
负责人：
Kimberly Stroka
金额：
$ 2.88万
依托单位：
UNIV OF MARYLAND, COLLEGE PARK
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-01-01 至 2011-12-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Cardiovascular disease (CVD) is the leading cause of death in the world. One type of CVD, atherosclerosis, typically occurs in regions of disturbed blood flow, and its onset results in the stiffening of arteries and the creation of raised plaques which increase the chance of complete artery blockage. If blood supply to the brain is stopped as a result of this blockage, stroke occurs. The biophysical aspects associated with the mechanical effects of artery stiffening and how they relate to immune function will be investigated simultaneously in the proposed research plan. The main hypothesis of this proposal is that the mechanisms of transendothelial migration (TEM) by immune cells are affected by the organization and stiffness of the endothelial cell (EC) layer. Three specific aims are proposed to investigate this hypothesis. The first aim is to design and characterize an in vitro model of the vascular endothelium. The morphology, protein expression, stiffness, traction forces, F-actin distribution, and focal adhesions of the ECs will be examined as the underlying stiffness and shear stress are varied. The second aim is to investigate leukocyte migration along the EC monolayer as a function of underlying stiffness and shear stress. Leukocyte migration along the EC layer will be quantified using several parameters such as speed, random motility coefficient, and distribution of turning angles, and the traction forces exerted by the ECs will also be quantified as a measure of changes in force transmission through the ECs. The third aim is to investigate leukocyte TEM through ECs as a function of underlying stiffness and shear stress. The effects of leukocyte TEM on EC mechanotransmission will be investigated by examining the traction forces, F-actin distribution, and focal adhesions of the ECs. With the completion of the proposed research plan, we will more fully understand the role the ECs play as force transmitters during cellular TEM, and how this process might be altered in stiffened, atherosclerotic tissue. Stroke is a type of cardiovascular and neurological disease which often occurs due to blockage and stiffening of the arteries leading to the brain. This proposal investigates how stiffened, atherosclerotic tissue might affect immune cell migration into the diseased arteries, and how forces are transmitted through the vascular endothelium during this process. Ultimately, our goal is to find better ways to predict onset of a stroke before it occurs, so that treatment may be possible.

描述（由申请人提供）：心血管疾病（CVD）是世界上死亡的主要原因。一种类型的CVD，动脉粥样硬化通常发生在受干扰的血流区域，其发作导致动脉僵硬和凸起的斑块的产生，从而增加了完全动脉阻塞的机会。如果由于这种阻塞而停止了对大脑的血液供应，则会发生中风。在拟议的研究计划中，将同时研究与动脉僵硬及其与免疫功能相关的机械作用及其与免疫功能相关的生物物理方面。该提议的主要假设是免疫细胞的跨内皮迁移（TEM）机理受到内皮细胞（EC）层的僵硬的影响。提出了三个具体目标来研究这一假设。第一个目的是设计和表征血管内皮的体外模型。随着潜在的刚度和剪切应力的变化，将检查形态，蛋白质表达，刚度，牵引力，F-肌动蛋白分布和EC的局灶性粘附。第二个目的是研究白细胞沿EC单层的迁移，这是潜在的刚度和剪切应力的函数。沿EC层的白细胞迁移将使用多个参数进行量化，例如速度，随机运动系数和转弯角的分布，ECS施加的牵引力也将被量化为通过ECS力传递的变化的量度。第三个目的是通过ECS研究白细胞TEM，这是潜在的刚度和剪切应力的函数。通过检查EC的牵引力，F-肌动蛋白分布和局灶性粘附，将研究白细胞TEM对EC机械传递的影响。随着拟议的研究计划的完成，我们将更充分理解EC在细胞TEM期间作为力发射器的作用，以及在僵硬的动脉粥样硬化组织中如何改变该过程。中风是一种心血管和神经系统疾病，通常是由于导致大脑的动脉阻塞和僵硬而发生的。该提案调查了如何僵硬，动脉粥样硬化的组织可能影响免疫细胞向患病动脉迁移，以及在此过程中如何通过血管内皮传播力。最终，我们的目标是找到更好的方法来预测中风的发作，以便可以进行治疗。