Caveolin-1, Caveolae and Placental Angiogenesis

Caveolin-1、Caveolae 和胎盘血管生成

基本信息

批准号：
7240598
负责人：
DONGBAO CHEN
金额：
$ 5.4万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-07-01 至 2008-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7240598
关键词：
Address Arteries Binding Biological Availability Biology Blood Circulation Blood Vessels Blood capillaries Blood flow Capillary Endothelial Cell Caveolae Cell Cycle Cell Line Cell Proliferation Cell Survival Cell model Cells Clinical Data Disease Disruption Down-Regulation Eclampsia Ectopic Expression Endothelial Cells Epidermal Growth Factor Receptor Epitopes Event Family member Fetal Development Fetal Growth Fetal Growth Retardation Functional disorder Gene Family Genetic Green Fluorescent Proteins Growth Growth Factor Healed Hemagglutinin Human In Vitro Interphase Cell Knockout Mice Lead Length Ligands Link Localized Lung MEKs Mediating Medicine Membrane Methods Mitogen-Activated Protein Kinases Mitogens Modeling Molecular Neuropilin-1 Nitric Oxide Nitric Oxide Synthase Normal tissue morphology Nutrient Organelles Oxygen Pathologic Pathway interactions Perfusion Phosphorylation Phosphotransferases Placenta Platelet-Derived Growth Factor Receptor Play Pre-Eclampsia Pregnancy Process Production Protein Kinase Protein Overexpression Protein Tyrosine Kinase Proteins Proto-Oncogene Proteins c-akt Ras/Raf Regulation Reproductive Biology Research Residual state Role Scaffolding Protein Signal Pathway Signal Transduction Signal Transduction Pathway Signaling Molecule Small Interfering RNA Source Structure Tertiary Protein Structure Time Tissues Tube Tumor Tissue VEGFA gene Vascular Endothelial Growth Factor Receptor Vascular Endothelial Growth Factor Receptor-1 Vascular Endothelial Growth Factor Receptor-2 Vascular Endothelial Growth Factors Vascular Permeabilities Vascular System Vasodilation Vasodilation disorder angiogenesis autocrine capillary caveolin 1 cell type clinically relevant extracellular fetal healing human NOS3 protein in vivo innovation insight migration novel novel therapeutics paracrine receptor scaffold src-Family Kinases uptake

项目摘要

DESCRIPTION (provided by applicant): The overall hypothesis is that caveolin-1 (cav-1) interacts with vascular endothelial growth factor (VEGF) receptors (VEGFR) directly and/or indirectly to concentrate VEGFR initiated signaling events, i.e., Ras-Raf-MEK1-ERK2/1 and PI3K/Akt signaling modules, in the caveolae of endothelial cells (EC), thereby modulating VEGF regulation of EC proliferation, migration, and differentiation. Moreover, cav-1/caveolae may regulate placental angiogenesis by modifying the bioavailability of nitric oxide (NO) in EC. To address this hypothesis, an ovine fetoplacental artery EC model and a human placental capillary endothelial cell line will be used. Specific Aim 1: To further clarify if VEGFRs (i.e., KDR, Flt-1, and NP-1) are physically associated with cav-1 in vitro and in vivo, thus localized in the caveolae, and if overexpression of exogenous cav-1 or targeted down-regulation of endogenous cav-1 regulates ligand-dependent VEGFR activation. Specific Aim 2: To determine if targeted down-regulation of endogenous cav-1 or overexpression of exogenous cav-1 alters VEGF stimulation of cell cycle entry, proliferation, migration and differentiation. Specific Aim 3: To determine if VEGF activates the Ras/Raf/ERK2/1 and PI3K/Akt signaling modules in the caveolae. Specific Aim 4: To delineate if down-regulation of cav-1 or cav-1 overexpression modulates VEGF stimulation of MAPK and PI3K/Akt signaling pathways and the role of these pathways in VEGF-induced cell cycle entry, cell proliferation, migration, and differentiation. Specific Aim 5: To determine if targeted down-regulation of endogenous cav-1 or overexpresison of exogenous cav-1 alters eNOS activity thereby altering the bioavaibility Iof NO, which in turn regulates placental angiogenesis. These studies will have a great impact on our understanding of caveoli, VEGF/VEGFR, endothelial, and angiogenesis biology, all are biologically important fields we have integrated in the proposal clinically relevant to placental angiogenesis and vasodilatation for the first time. The ultimate clinical importance of this research is evident when one considers that uteroplacental endothelial adaptations to pregnancy, especially the rises in fetoplacental and uteroplacental perfusion, are linked directly to fetal growth and survivability and that these mechanisms are dysfunctional in pathologic pregnancies such as preeclampsia and IUGR.

DESCRIPTION (provided by applicant): The overall hypothesis is that caveolin-1 (cav-1) interacts with vascular endothelial growth factor (VEGF) receptors (VEGFR) directly and/or indirectly to concentrate VEGFR initiated signaling events, i.e., Ras-Raf-MEK1-ERK2/1 and PI3K/Akt signaling modules, in the caveolae of endothelial cells (EC), thereby调节VEGF对EC增殖，迁移和分化的调节。此外，CAV-1/Caveolae可以通过修改EC中一氧化氮（NO）的生物利用度来调节胎盘血管生成。为了解决这一假设，将使用卵胎胎盘型动脉模型和人胎盘毛细管内皮细胞系。具体目的1：进一步阐明VEGFR（即KDR，FLT-1和NP-1）在物理上与Cav-1体外和体内有物理相关，因此位于小窝中，以及外源性CAV-1的过度表达或靶向的内源性CAV-1对内源性CAV-1的下调调节依赖依赖的VEGFR FEVFFR FEVFR FELFFR EXTICATION。具体目标2：确定内源性CAV-1的靶向下调或外源CAV-1的过表达会改变VEGF刺激细胞周期进入，增殖，迁移和分化。特定目标3：确定VEGF是否激活Caveolae中的RAS/RAF/ERK2/1和PI3K/AKT信号模块。具体目的4：描述CAV-1或CAV-1过表达的下调是否会调节MAPK和PI3K/AKT信号通路的VEGF刺激，以及这些途径在VEGF诱导的细胞周期进入，细胞增殖，迁移和差异化中的作用。具体目的5：确定靶向下源性CAV-1的靶向下调或外源Cav-1的过度主张会改变eNOS活性，从而改变IOF no的生物可挽救性，从而调节胎盘血管生成。这些研究将对我们对口腔，VEGF/VEGFR，内皮和血管生成生物学的理解产生很大的影响，这都是我们在临床上与胎盘血管生成和血管扩张有关的临床中首次融合的生物学重要领域。当人们认为对怀孕的子宫内皮适应，尤其是胎儿乳突和子宫乳酸灌注的升高时，这项研究的最终临床重要性显而易见，与胎儿的生长和生存能力直接相关，并且这些机制在诸如preeclampsia和igeclampsia之类的病理妊娠中是功能障碍的。