Distinct Pathways of VPF/VEGF Receptors

VPF/VEGF 受体的独特途径

• 批准号: 8193287
• 负责人: DEBABRATA MUKHOPADHYAY
• 金额: $ 39.43万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8193287
• 关键词: Acute; Address; Angiogenesis Inhibitors; Angiogenesis Promoter; Biological Assay; Biological Models; Blood Vessels; Cardiovascular Diseases; Cell Differentiation process; Cell Proliferation; Characteristics; Chronic; Clear Cell; Complex; Development; Diabetic Retinopathy; Disease; Employee Strikes; Endothelial Cells; Equilibrium; Experimental Designs; Funding; Future; Genetic; Heart Diseases; Heating; Human; In Vitro; Individual; Inflammatory; Knowledge; Lead; Maintenance; Malignant Neoplasms; Maps; Mediating; Mediator of activation protein; Modeling; Molecular; Monitor; Neuropilin-1; Neuropilin-2; Neuropilins; Nutrient; Organ; Organism; Pathology; Pathway interactions; Permeability; Phosphotransferases; Physiological Processes; Play; Process; Receptor Protein-Tyrosine Kinases; Regulation; Role; Signal Pathway; Signal Transduction; Stem cells; Stroke; Time; Tissues; Transgenic Organisms; Tumor Angiogenesis; Vascular Diseases; Vascular Endothelial Growth Factor Receptor; Vascular Endothelial Growth Factors; Vascular Permeabilities; Vascular System; Venous; Vertebrates; Waste Products; Wound Healing; Zebrafish; angiogenesis; bone cell; cell fate specification; cell type; cytokine; human embryonic stem cell; improved; in vivo; migration; nerve stem cell; protein kinase D; receptor; response; small molecule; tumor; tumor growth

DESCRIPTION (provided by applicant): The long-term objective of our proposal is to elucidate the signaling pathways by which vascular permeability factor/vascular endothelial growth factor (VPF/VEGF, VEGF-A) promotes blood vessel formation and influences microenvironment. VEGF-A participates in a variety of vascular processes including endothelial cell (EC) proliferation, migration, survival, and differentiation (arterial-venous cell fate specification) through its two tyrosine kinase receptors, VEGFR-1 and VEGFR-2 and non-tyrosine kinase receptors neuropilins (NRPs). During the last two cycles of our funding, we defined several diverse and complex pathways of VEGF-A. These pathways focused mainly on proliferation, migration, and survival. Although there is striking evidence for distinct functional roles of VEGF-A-mediated signaling through VEGF receptors (VEGFRs), it is still unclear how certain VEGF-mediated downstream signal transduction cascades selectively potentiate two important functions: promotes EC differentiation and creates EC hyperpermeability. To understand the unique signaling pathways of VEGF-A, we have proposed two aims. Aim 1 will delineate the roles of VEGFR-2 and NRPs for EC differentiation. We will also define the signaling pathways of VEGF-mediated p53 regulation and its role in EC differentiation. Similarly, the key role of Protein Kinase D (PKD) in VEGF-mediated EC differentiation will be evaluated. Whereas, Aim 2 will define the molecular mechanism of VEGF-induced vascular permeability (VP) in real-time. Recently we have developed a heat-inducible VEGF-A transgenic zebrafish model to study VP in real-time. In this aim, we will evaluate the role of individual VEGFRs and the molecules downstream of the pathways that lead to three distinctly different settings: basal vascular permeability (BVP), acute vascular hyperpermeability (AVH), and chronic vascular hyperpermeability (CVH). The proposed studies will elucidate the signaling pathways by which the known as well as unknown molecules mediate the different types of vascular permeability. Hence, the results of the proposed studies will promote understanding of the molecular mechanisms and pathways of these two important functions of VEGF-A and will impact our knowledge of normal physiological processes such as wound healing as well as pathological conditions, including cancer, diabetic retinopathy, and ischemic conditions leading to heart disease and stroke. Lastly, the proposed studies will expand our understanding of VEGF-A signaling as it relates to other VEGF-responsive cell types including circulating progenitor cells, bone cells, and neuronal progenitors. PUBLIC HEALTH RELEVANCE: Vascular Permeability Factor/Vascular Endothelial Growth Factor (VPF/VEGF, VEGF-A) is arguably the most important angiogenic cytokine expressed by tumors, and it is expected that blocking VEGF-A signaling will be effective in controlling tumor angiogenesis and therefore limiting, or even reversing, tumor growth. On the other hand, there are several diseases in which we need to promote balanced angiogenesis including cardiovascular diseases. The proposed studies will map the critical signaling pathways responsible for two important functions of VEGF-A, endothelial cell (EC) differentiation and EC leakiness, and in the process identify key molecules that mediate these pathways. Hence, the results of the proposed studies will help us create more specific targets for potential angiogenesis inhibitors or promoters and can improve future therapies in various diseases including tumors, cardiovascular disease, and others.

描述（申请人提供）：我们提案的长期目标是阐明血管通透因子/血管内皮生长因子（VPF/VEGF、VEGF-A）促进血管形成并影响微环境的信号通路。 VEGF-A 通过其两种酪氨酸激酶受体 VEGFR-1 和 VEGFR-2 以及非酪氨酸激酶受体神经毡蛋白 (NRP) 参与多种血管过程，包括内皮细胞 (EC) 增殖、迁移、存活和分化（动静脉细胞命运规范）。在我们资助的最后两个周期中，我们定义了 VEGF-A 的几种多样化且复杂的途径。这些途径主要集中在增殖、迁移和生存。尽管有惊人的证据表明 VEGF-A 介导的信号通过 VEGF 受体 (VEGFR) 发挥独特的功能作用，但仍不清楚某些 VEGF 介导的下游信号转导级联如何选择性地增强两个重要功能：促进 EC 分化和产生 EC 高通透性。为了了解 VEGF-A 的独特信号通路，我们提出了两个目标。目标 1 将描述 VEGFR-2 和 NRP 在 EC 分化中的作用。我们还将定义 VEGF 介导的 p53 调节的信号通路及其在 EC 分化中的作用。同样，我们将评估蛋白激酶 D (PKD) 在 VEGF 介导的 EC 分化中的关键作用。而目标 2 将实时定义 VEGF 诱导血管通透性 (VP) 的分子机制。最近我们开发了一种热诱导 VEGF-A 转基因斑马鱼模型来实时研究 VP。为此，我们将评估单个 VEGFR 和通路下游分子的作用，这些分子会导致三种截然不同的情况：基础血管通透性 (BVP)、急性血管通透性过高 (AVH) 和慢性血管通透性过高 (CVH)。拟议的研究将阐明已知和未知分子介导不同类型血管通透性的信号传导途径。因此，拟议研究的结果将促进对 VEGF-A 这两个重要功能的分子机制和途径的理解，并将影响我们对正常生理过程（如伤口愈合）以及病理状况（包括癌症、糖尿病视网膜病变以及导致心脏病和中风的缺血性疾病）的了解。最后，拟议的研究将扩大我们对 VEGF-A 信号传导的理解，因为它与其他 VEGF 反应性细胞类型（包括循环祖细胞、骨​​细胞和神经元祖细胞）相关。 公共健康相关性：血管通透性因子/血管内皮生长因子（VPF/VEGF、VEGF-A）可以说是肿瘤表达的最重要的血管生成细胞因子，预计阻断 VEGF-A 信号传导将有效控制肿瘤血管生成，从而限制甚至逆转肿瘤生长。另一方面，有几种疾病需要促进平衡的血管生成，包括心血管疾病。拟议的研究将绘制负责 VEGF-A 两个重要功能（内皮细胞 (EC) 分化和 EC 渗漏）的关键信号通路，并在此过程中识别介导这些通路的关键分子。因此，拟议研究的结果将帮助我们为潜在的血管生成抑制剂或促进剂创建更具体的靶点，并可以改善包括肿瘤、心血管疾病等在内的各种疾病的未来治疗。