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.

项目总结