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Endothelial cell decisions integrate soluble and matrix-bound VEGF gradients

内皮细胞决策整合了可溶性和基质结合的 VEGF 梯度

基本信息

批准号：
7928769
负责人：
Feilim C Mac Gabhann
金额：
$ 24.87万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-10 至 2012-07-03
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7928769
关键词：
Adherence Age related macular degeneration Arteries Arts Binding Blood Vessels Cell Culture Techniques Cell Proliferation Cells Clinical Trials Computer Simulation Coronary Arteriosclerosis Decision Making Diabetic Retinopathy Diffuse Disease Embryonic Development Endothelial Cells Environment Equilibrium Exercise Experimental Designs Extracellular Matrix FDA approved Family Fibronectins Frequencies Genes Growth Factor In Vitro Integrins Laboratories Left Ligand Binding Domain Ligands Macular degeneration Malignant Neoplasms Masks Methods Modeling Morbidity - disease rate Mus Muscle Cells Pathogenesis Pathway interactions Pattern Peripheral arterial disease Process Proliferating Protein Isoforms Proteins Protocols documentation Public Health Receptor Activation Receptor Gene Receptor Protein-Tyrosine Kinases Regulation Relative (related person)Reproduction Research Role Signal Pathway Signal Transduction Skeletal Muscle Stimulus Techniques Testing The Sun Therapeutic Tissues Training Transfection Up-Regulation Vascular Endothelial Growth Factor Receptor Vascular Endothelial Growth Factors angiogenesis base cell motility cytokine density design extracellular genetic manipulation in vitro Assay in vivo inhibitor/antagonist migration mortality mutant neovascularization novel receptor research study response therapeutic target

项目摘要

PROJECT SUMMARY (See Instmctions): The vascular endothelial growth factor (VEGF) family consists of critical cytokines that are implicated in controlling vascular survival and angiogenic sprouting. Recently VEGF inhibitors have been approved by the FDA to treat diseases of hypervascularization (cancer and macular degeneration), while increasing VEGF expression is a major research avenue for ischemic diseases such as peripheral artery disease and coronary artery disease, though clinical trials are as yet unsuccessful. VEGF is involved in at least 70 diseases as either cause or therapeutic target Regulation of VEGF signaling is therefore of critical importance for many therapeutic strategies. Recent evidence suggests that more VEGF is bound to the extracellular matrix in vivo than freely diffuses, and that these matrix-binding isoforms of VEGF control branching frequency and network density in vivo. The presentation of VEGF to the receptors by a matrix molecule may initiate a distinct signaling mode, but traditional in vitro cell culture models are unable to differentiate the soluble VEGF signal from the matrix-bound VEGF signal. In this proposal, we develop a combined experimentalcomputational approach to separate the soluble and matrix-bound VEGF signals. Using novel or available fibronectin mutants that do not bind VEGF (Aim 1), we will use state-of-the-art micropatteming techniques to plate endothelial cells on a substrate with gradients of VEGF binding ability (Aim 2). In vitro assays of proliferation, migration and survival will definitively show whether soluble VEGF or matrix-bound VEGF is the more potent stimulator of these critical endothelial cell decisions (Aim 2). We then propose to use in vivo transfection techniques to increase VEGF gradients and to block presentation of matrix-bound VEGF to receptor tyrosine kinases in vivo (Aim 3). This will test whether the in vitro endothelial cell culture is a good model of the decision-making of endothelial cells in vivo.

项目概述（见说明）：