Distinct Pathways of VPF/VEGF Receptors

描述（申请人提供）：我们提案的长期目标是阐明血管渗透性因子/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纤毛蛋白（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（动脉-静脉细胞命运特化）。在过去的两个资助周期中，我们确定了VEGF-A的几个不同而复杂的途径。这些途径主要集中在增殖，迁移和生存。虽然有明显的证据表明，VEGF-A介导的信号转导通过VEGF受体（VEGF）的不同功能的作用，它仍然不清楚某些VEGF介导的下游信号转导级联如何选择性地加强两个重要的功能：促进EC分化和创建EC高通透性。为了了解VEGF-A独特的信号通路，我们提出了两个目标。目的1阐明VEGFR-2和NRP在EC分化中的作用。我们还将确定VEGF介导的p53调控的信号通路及其在EC分化中的作用。类似地，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诱导的血管通透性（VP）的分子机制。最近，我们建立了一个热诱导VEGF-A转基因斑马鱼模型来实时研究VP。在这一目标中，我们将评估单个VEGF受体和导致三种明显不同的设置的途径下游的分子的作用：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的血管通透性的信号通路。因此，拟议研究的结果将促进对VEGF-A这两种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的认识，如伤口愈合以及病理条件，包括癌症，糖尿病视网膜病变和导致心脏病和中风的缺血性疾病。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响应细胞类型（包括循环祖细胞、骨细胞和神经元祖细胞）有关。

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.