ECM and shear stress

ECM 和剪切应力

• 批准号: 10192388
• 负责人: Martin A Schwartz
• 金额: $ 52.05万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-10 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10192388
• 关键词: 1-Phosphatidylinositol 3-Kinase; Affect; Antibodies; Arteries; Biology; Blood Vessels; Blood flow; Caliber; Cells; Cessation of life; Coronary; Coronary Arteriosclerosis; Cyclic AMP; Data; Developed Countries; Disease; Disease model; Endothelial Cells; Endothelium; Event; Extracellular Matrix; Family; Fibronectins; Future; Goals; Grant; Hindlimb; Human; ITGA5 gene; In Vitro; Inflammation; Inflammatory; Integrins; Ischemia; KDR gene; Link; Liquid substance; MicroRNAs; Molecular; Mus; Myocardial Infarction; Outcome; Pathway interactions; Patients; Peripheral; Peripheral arterial disease; Phenotype; Physiological; Process; Publishing; Reagent; Recombinant Antibody; Recovery; Resolution; Role; Signal Pathway; Signal Transduction; Testing; Therapeutic; Tissues; Transforming Growth Factor beta; base; improved; in vivo; interest; novel strategies; patient subsets; programs; receptor; response; shear stress; tool

Project Summary Poor arteriogenesis, in which blood vessels parallel to an arterial blockage fail to remodel to restore blood flow to the affected tissue, is a major factor in illness and death in peripheral and coronary artery disease. This project is based on the hypothesis that arteriogenesis is initiated by elevated shear stress in small blood vessels that triggers a sequence of endothelial activation, inflammation, matrix remodeling, vessel expansion and resolution, which returns shear levels toward normal and restores normal vessel function. Artery remodeling is thus governed by a fluid shear stress set point such that when shear stress goes above or below the optimal range, ECs trigger a response to change vessel diameter and return shear toward the original value. The overall goal of this grant is to elucidate these mechanisms in more detail and identify restriction points that inhibit arteriogenesis in disease. Our preliminary and published data implicate extracellular matrix remodeling and smad activation as key components of these processes. Based on these results, we will: 1) Elucidate the role of matrix remodeling in arteriogenesis, specifically examining whether blocking a link between fibronectin and inflammatory pathways improve arteriogenesis in disease models. 2) Elucidate the signaling networks that govern the fluid shear stress set point. 3) Develop antibody- based tools that specifically alter the effects of flow on activation of Smad 2/3 vs Smad 1/5/8, and test their effects on arteriogenesis.

项目摘要 动脉生成不良，与动脉阻塞平行的血管无法重塑恢复 血流到受影响的组织，是外周动脉和冠状动脉疾病和死亡的主要因素 疾病该项目基于动脉生成是由升高的剪切应力启动的假设 在小血管中引发一系列内皮激活、炎症、基质 重塑、血管扩张和消退，使剪切水平恢复正常， 正常的血管功能。因此，动脉重塑由流体剪切应力设定点控制，使得 当剪应力高于或低于最佳范围时，EC触发改变血管的反应， 直径和返回剪切向原始值。这项资助的总体目标是阐明这些 更详细的机制，并确定限制点，抑制动脉生成的疾病。我们 初步和公开的数据暗示细胞外基质重塑和Smad激活是关键 这些过程的组成部分。基于这些结果，我们将：1）阐明基质的作用 动脉生成中的重塑，特别是检查是否阻断纤连蛋白和血管生成之间的联系， 炎症途径改善疾病模型中的动脉生成。 2)阐明控制流体剪切应力设定点的信号网络。3)产生抗体- 基于工具，专门改变流动对Smad 2/3与Smad 1/5/8激活的影响，以及 测试它们对动脉生成的影响。