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Role of Syntaxin 6 Regulated Post-Golgi Trafficking in Angiogenesis

突触融合蛋白 6 调节高尔基体后运输在血管生成中的作用

基本信息

批准号：
8292015
负责人：
Amit Choudhury
金额：
$ 33.41万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-10 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8292015
关键词：
Address Affect Antibodies Antisense Oligonucleotides Attenuated Binding Biological Biological Models Cell Proliferation Cell membrane Cell physiology Cell surface Cell-Cell Adhesion Cell-Matrix Junction Cells Chimeric Proteins Cholesterol Coupled Data Disease Ear Ectopic Expression Endocytosis Endothelial Cells Epitopes Equilibrium Event Exposure to Fluorescence Fluorescence Recovery After Photobleaching Focal Adhesions Foundations Functional disorder Glycosphingolipids Goals Golgi Apparatus Health Human In Vitro Inflammatory Integrins Knockout Mice Knowledge Lead Life Lipids Lung Maintenance Malignant - descriptor Maps Mediating Membrane Membrane Biology Membrane Fusion Membrane Lipids Membrane Protein Traffic Microscopy Modeling Molecular Morphogenesis Mus PTK2 gene Pathway interactions Phosphotransferases Play Process Proteins Regulation Research Proposals Role SRC gene Signal Transduction Signaling Molecule Signaling Protein Sphingolipids Sterols System Techniques Testing Toxin Transmembrane Transport Tube Umbilical vein Vascular Endothelial Growth Factor A Vascular Endothelial Growth Factor Receptor-2 Vascular Endothelial Growth Factors Vesicle angiogenesis caveolin 1 cell fixing cell growth regulation cell motility cell type cellular imaging in vivo in vivo Model loss of function mouse model novel paxillin protein activation receptor response rho GTP-Binding Proteins src-Family Kinases syntaxin 6 trafficking

项目摘要

Title: Role of syntaxin 6 regulated post-Golgi trafficking in angiogenesis Angiogenesis refers to the establishment of new vessels from preexisting vasculature. Dysfunctions in angiogenesis can lead to several malignant, inflammatory, and ischemic disorders. New vessel formation involves multiple cellular processes, including cellular proliferation and migration, cell-cell and cell-matrix adhesion interactions, and tube morphogenesis. "Membrane rafts" are regions of the plasma membrane that are enriched in sphingolipids and sterols. These domains are also enriched in signaling proteins including certain kinases, integrins and vascular endothelial growth factor receptor-2 (VEGFR2), all of which are believed to play roles in angiogenesis. To date, the roles that membrane rafts and the intracellular trafficking of associated components play in angiogenesis remain unclear. We have previously identified a novel role for the vesicle fusion protein syntaxin 6 (syn6) in the delivery of raft-associated lipids and proteins to the plasma membrane (PM). Our long-term objective is to understand the mechanism(s) by which the trafficking of membrane raft components influences cell motility. The overall goals of this research proposal are to define the molecular mechanisms that underlie inside-out trafficking and the delivery of "membrane raft" components to the endothelial cell surface, and to examine the importance of these processes in the regulation of cellular motility during angiogenesis. Collectively, our group has expertise in multiple loss-of-function approaches, live- cell imaging, molecular and cell biological techniques, and several in vitro and in vivo angiogenesis models, and this will allow us to address these important questions in endothelial cells. In Aim 1, we will use in vitro studies to assess how cell motility is affected by syn6-dependent modulation of membrane raft composition at the PM. To this end, we will evaluate the membrane domain formation, recruitment, organization, activation, and dynamics of focal adhesion-associated proteins. In Aim 2, we will perform in vitro studies to unravel the molecular mechanism behind secretory transport and delivery of VEGFR2 to the PM. In Aim 3, we will use both in vitro and in vivo model systems to test the functional significance of syn6-regulated trafficking of membrane raft components generally, and of VEGFR2 more specifically, with respect to endothelial tube morphogenesis and angiogenesis. Findings from these studies will begin to unravel the mechanisms by which syn6-mediated membrane trafficking regulate angiogenesis, and may provide novel candidate targets for pro- or anti- angiogenic therapies. Angiogenesis involves the formation of new vessels from preexisting ones, and plays an important role in health and several diseases. Signaling via the cell surface-localized vascular endothelial growth factor receptor-2 (VEGFR2) and "membrane rafts" plays key role in angiogenesis. However, our knowledge about the trafficking pathways involved in the maintenance of VEGFR2 and raft component localization to the cell surface is limited. By studying and understanding the trafficking of angiogenesis-regulatory molecules, we may identify a novel target for therapy.

标题：syntaxin 6在血管生成过程中调节高尔基转运的作用