MOLECULAR BASIS OF ENDOTHELIAL REMODELING BY FLOW

流动内皮重塑的分子基础

• 批准号: 6184688
• 负责人: SHU CHIEN
• 金额: $ 65.83万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-28 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6184688
• 关键词: atherosclerosis; bioengineering /biomedical engineering; cell growth regulation; cell migration; cell proliferation; disease /disorder model; fluid flow; gene induction /repression; genetic regulation; genetic techniques; hemodynamics; mechanical stress; molecular dynamics; molecular film; tissue /cell culture; vascular endothelium

Hemodynamic forces regulate the structure and function of the blood vessel wall. Vascular endothelial cells (ECs) are exposed to shear stress, the tangential component of the hemodynamic forces acting on the vessel wall. ECs in the straight part of the arterial tree are subjected to laminar flow with high shear stress, whereas cells in the bends and bifurcations are under disturbed patterns with low shear stress but high shear stress gradient. Our hypothesis is that the preferential localization of atherosclerosis in the branch points of the arterial tree and the sparing of the straight parts can be related to the different molecular responses to these flow patterns. The laminar flow in the straight part of the vessels is anti-atherogenic by arresting the EC cell cycle. In contrast, disturbed flow at branch points is pro-atherogenic by increasing EC proliferation. Laminar flow enhances the repair of the dysfunctional endothelium by augmenting EC migration, in comparison to disturbed flow. We will test our hypothesis that laminar flow and disturbed flow activate different molecular signaling pathways to result in the expression of unique sets of genes, thus leading to the functional consequences of anti-atherosclerosis and pro- atherosclerosis, respectively. The research design has three Specific Aims. In Specific Aim 1, we will establish the molecular basis of the regulation of EC cell cycle by different flow patterns. In Specific Aim 2, we will elucidate the molecular mechanisms by which EC migration is modulated by laminar and disturbed flows. In Specific Aim 3, we will identify the genes regulated by laminar flow and disturbed flow by using DNA microarray technology, with the aim of guiding in-depth studies on the flow-responsive genes that modulate EC cell cycle and migration. The proposed research involves partnership among scientists with expertise in vascular biology, physiology, biomechanics, bioengineering, bioinformatics, cell biology, and molecular biology. This interdisciplinary research program will allow us to elucidate the molecular basis of flow-induced modulation of EC turnover and migration, which are two important processes for vascular remodeling. The results from this BRP application will serve to generate new knowledge on mechano- transduction and vascular biology, provide new understanding of the molecular and biomechanical bases of pathogenesis of vascular disorders such as atherosclerosis, and help to develop new therapeutic strategies.

血流动力调节血管壁的结构和功能。 血管内皮细胞 (EC) 暴露于剪切应力，即作用于血管壁的血流动力学的切向分量。 动脉树直线部分的内皮细胞受到高剪切应力的层流作用，而弯曲和分叉处的细胞则受到低剪切应力但高剪切应力梯度的干扰模式。 我们的假设是，动脉粥样硬化优先定位于动脉树的分支点，而直的部分则不受影响，可能与这些血流模式的不同分子反应有关。 血管直线部分的层流通过阻止 EC 细胞周期来抗动脉粥样硬化。 相反，分支点的血流紊乱会增加 EC 增殖，从而导致动脉粥样硬化。 与扰动流相比，层流通过增强 EC 迁移来增强功能失调的内皮细胞的修复。 我们将检验我们的假设，即层流和扰动流激活不同的分子信号传导途径，导致独特基因组的表达，从而分别导致抗动脉粥样硬化和促动脉粥样硬化的功能后果。 研究设计有三个具体目标。 在具体目标1中，我们将建立不同流动模式调节EC细胞周期的分子基础。 在具体目标 2 中，我们将阐明层流和扰动流调节 EC 迁移的分子机制。 在具体目标3中，我们将利用DNA微阵列技术识别层流和扰动流调控的基因，旨在指导对调节EC细胞周期和迁移的流动响应基因的深入研究。 拟议的研究涉及具有血管生物学、生理学、生物力学、生物工程、生物信息学、细胞生物学和分子生物学专业知识的科学家之间的合作。 这项跨学科研究计划将使我们能够阐明血流诱导的 EC 周转和迁移调节的分子基础，这是血管重塑的两个重要过程。 BRP 应用的结果将有助于产生关于机械传导和血管生物学的新知识，提供对动脉粥样硬化等血管疾病发病机制的分子和生物力学基础的新认识，并有助于开发新的治疗策略。