Akt Signaling Pathways in VEGF-A-induced Angiogenesis

VEGF-A 诱导的血管生成中的 Akt 信号通路

• 批准号: 8378435
• 负责人: LAURA E BENJAMIN
• 金额: $ 29.24万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 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/8378435
• 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; 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; tool; transcription factor; tumor; venule

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.

为了超出最小尺寸，肿瘤必须产生新的血管。 VEGF-A，大多数人表达 恶性肿瘤主要负责肿瘤血管生成，并具有不寻常的特性 激活Ca2+级联反应并诱导血管过敏性的血管生成因子。 超重性是新形成的肿瘤血管的特征，具有重要作用 N肿瘤血管生成和基质形成。由VEGF-A分泌肿瘤诱导的新血管 至少有6种不同的类型，并且使用设计用于表达VEGF-A164的腺病毒矢量，我们有 能够在各种普通小鼠组织中产生每种血管类型的替代形式。的 几种类型的肿瘤血管，母血（MV）是第一个形成的，是主要的 可渗透的容器子集。 MV大大扩大，贫穷的正弦曲线，过表达VEGFR-1 和-2;它们也是在许多快速生长的小鼠肿瘤中发现的最常见的血管类型，并且 在人类肿瘤中也很常见。我们发现，VEGF-A的大部分血管生成活动是 通过孤儿核转录因子TR3（人）/NUR77（小鼠）介导。我们的整体 假设是TR3/NUR77在调节VEGF-A诱导的血管中具有重要的至关重要的作用 渗透性，血管超微结构和最早的肿瘤血管生成阶段，导致形成 可渗透的母船。两个具体目标将检验以下中心假设：目标1。量化 NUR77表达水平对血管通透性，血管超微结构和血管生成的影响， 利用野生型和工程的NUR77 - / - 和转基因NUR77-S小鼠，并瞄准2。阐明 激活Ca2+并调节TR3表达和转录活性的信号通路 在体内培养的内皮细胞和Matrigel插头测定中。这些目标利用不同的技术 专注于一个目标，阐明VEGF-A诱导TR3/NUR77的步骤和机制 表达和激活，因此血管生成以及相关的血管过敏性。 与公共卫生的相关性：这些研究将阐明肿瘤启动形成的机制 他们需要生长和生存所需的新血管，并在此过程中识别出新的Potentia 攻击肿瘤脉管系统的靶标和干预点。