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Molecular Dissection of the Angiogenic Response Induced by VEGF-A

VEGF-A 诱导的血管生成反应的分子剖析

基本信息

批准号：
8259224
负责人：
HAROLD FISHER DVORAK
金额：
$ 30.97万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-06-13 至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8259224
关键词：
Acute Address Adenovirus Vector Adult Angiogenic Factor Applications Grants Avastin Biological Assay Blood Vessels Calcineurin Cancer Control Cells Characteristics Chronic Collaborations DNA Sequence Rearrangement Data Daughter Defect Discontinuous Capillary Dissection Endothelial Cells Engineering Event Exhibits Exposure to Extravasation Fibroblast Growth Factor 2 Genes Growth Growth Factor Head Histamine Histone Deacetylase Human Inflammation Inflammatory Intervention Knockout Mice Laboratories Lead Learning Literature Malignant Neoplasms Mediating Mesenchymal Microvascular Proliferation Modeling Molecular Mothers Mus NR4A1 gene Neoplasms in Vascular Tissue Nuclear Orphan Pathologic Neovascularization Pathway interactions Pericytes Permeability Phase Phosphoric Monoester Hydrolases Phosphorylation Physiological Plasma Plasma Proteins Platelet-Derived Growth Factor Play Process Property Protein Dephosphorylation Public Health Publications Rattus Regulation Rest Role Serotonin Signal Pathway Signal Transduction Structure System Technology Terminology Testing Tissues Transgenic Mice Transgenic Organisms Tumor Angiogenesis Vascular Endothelial Growth Factor Receptor Vascular Endothelial Growth Factor Receptor-1 Vascular Endothelial Growth Factor Receptor-2 Vascular Endothelial Growth Factors Vascular Endothelium Vascular Permeabilities Work Wound Healing analog angiogenesis in vivo macromolecule matrigel orphan nuclear receptor TR3 overexpression promoter research study response tool transcription factor tumor venule

项目摘要

To grow beyond minimal size, tumors must generate new blood vessels. VEGF-A, expressed by most malignant tumors is primarily responsible for tumor angiogenesis and has the unusual property among angiogenic factors of activating the Ca2+ cascade and inducing vascular hyperpermeability. Hyperpermeability is a characteristic feature of newly formed tumor blood vessels and has an important role n tumor angiogenesis and stroma formation. The new blood vessels induced by VEGF-A-secreting tumors are of at least 6 distinct types and, using an adenoviral vector engineered to express VEGF-A164, we have been able to generate surrogate forms of each vessel type in a variety of normal mouse tissues. Of the several types of tumor blood vessels, mother vessels (MV) are the first to form and are the primary hyperpermeable vessel subset. MV are greatly enlarged, pericyte-poor sinusoids that overexpress VEGFR-1 and -2; they are also the commonest type of blood vessel found in many rapidly growing mouse tumors, and are also common in human tumors. We have found that much of VEGF-A's angiogenic activities are mediated through an orphan nuclear transcription factor, TR3 (human)/Nur77 (mouse). Our overall hypothesis is that TR3/Nur77 has a central, essential role in regulating VEGF-A-induced vascular permeability, vascular ultrastructure and the earliest phase of tumor angiogenesis that leads to the formation of hyperpermeable mother vessels. Two Specific Aims will test this central hypothesis: Aim 1. Quantify the effects of Nur77 expression levels on vascular permeability, vascular ultrastructure and angiogenesis, making use of wild type and engineered Nur77-/- and transgenic Nur77-S mice, and Aim 2. Elucidate the signaling pathways that activate Ca2+ and that regulate TR3 expression and transcriptional activity in cultured endothelial cells and in Matrigel plug assays in vivo. These Aims make use of different technologies to focus on a single objective, elucidating the steps and mechanisms by which VEGF-A induces TR3/Nur77 expression and activation, and so angiogenesis and associated vascular hyperpermeability. Relevance to public health: These studies will clarify the mechanisms by which tumors initiate the formation of the new blood vessels they require for growth and survival and, in the process, identify new potentia targets and points of intervention for attacking the tumor vasculature.

肿瘤要长到最小，就必须产生新的血管。VEGF-A，大多数人表达