Spatial cues for retinal angiogenesis

描述(申请人提供)：视网膜血管容易受损，导致严重的眼部疾病，包括失明。虽然血管生成疗法正在被探索作为潜在的治疗方法，但一个重要的障碍是我们无法控制血管生成因子诱导的血管网络的三维组织，以确保药物诱导的视网膜血管系统的正常功能。因此，我们的长期目标是解开控制视网膜血管床空间组织的机制，特别是研究低氧信号通路的组成部分如何作为空间线索来确定视网膜血管生长的方向和位置。这些研究将在三个具体目标下进行。目的1.研究Pro羟基酶结构域蛋白在视网膜血管构型形成中的作用。PHD对缺氧诱导因子(HIF)的丰度具有负性调节作用，后者对血管生成至关重要。我们假设，组织微环境中PHD活性的水平决定了其附近血管生长的活性和方向性，并将通过产生包含PHD缺乏或过度表达的微组织结构域的嵌合视网膜来检验这一假设。目的2.确定HIF-1α在微组织区域的积聚是否控制附近组织中血管生长的位置和方向。目的3.探讨VEGFR-1在确定血管到血管距离中的作用。VEGFR-1由血管内皮细胞产生，与缺氧诱导的血管生成关键分子血管内皮生长因子-A形成紧密的复合体。我们认为，VEGF-A/VEGFR-1的相互作用减少了VEGFR-1表达来源附近的生物可用VEGF-A，因此不允许在与现有微血管一定距离内生长更多的微血管。这一假说将通过创建包含过度表达VEGFR-1的微组织域的嵌合视网膜并评估此类组织附近的血管密度来检验。这些研究的目的是促进旨在修复受损视网膜血管床的有效疗法的开发，并与国家眼科研究所(NEI)的使命高度一致。公共卫生相关性：视网膜中的血管损伤与许多严重的眼部疾病有关，包括视力丧失。本申请中提出的研究旨在加强我们对控制视网膜血管系统空间组织的分子通路的了解，从而帮助开发修复视网膜血管的治疗方法。

DESCRIPTION (provided by applicant): The retinal vasculature is prone to damages, leading to serious ocular diseases including loss of vision. While angiogenic therapies are being explored as potential treatments, a significant hurdle is our inability to control the three dimensional organization of the vascular network induced by angiogenic factors to ensure proper functioning of pharmacologically induced retinal vasculature. Thus, our long term objective is to unravel mechanisms that control the spatial organization of retinal vascular beds, and in particular to investigate how components of the hypoxia signaling pathway act as spatial cues to determine the direction and position of vascular growth in the retina. These studies will be carried out in three specific aims. Aim 1. Investigate roles of prolyl hydroxylase domain proteins in controlling retinal vascular pattern formation. PHDs negatively regulate the abundance of hypoxia inducible factors (HIFs), the latter of which are essential for angiogenesis. We hypothesize that the level of PHD activity in a tissue microenvironment determines the activity and directionality of vascular growth in its vicinity, and will test this hypothesis by generating chimeric retinas that contain micro tissue domains with PHD deficiency or overexpression. Aim 2. Determine if HIF-1 alpha accumulation in a micro tissue domain controls the position and direction of vascular growth in nearby tissues. Aim 3. Explore the role of VEGFR-1 in defining vessel to vessel distances. VEGFR-1 is produced by endothelial cells and forms tight complex with VEGF-A, a key angiogenic molecule induced by hypoxia. We propose that VEGF-A/VEGFR-1 interaction diminishes bioavailable VEGF-A near the source of VEGFR-1 expression and therefore disallows the growth of more microvessels within a certain distance from an existing microvessel. This hypothesis will be tested by creating chimeric retinas that contain micro tissue domains overexpressing, VEGFR-1, and assessing vascular density near such tissues. The objective of these studies is to facilitate the development of effective therapies aimed at repairing damaged retinal vascular beds and is highly consistant with the bmission of the National Eye Institute (NEI). PUBLIC HEALTH RELEVANCE: Vascular damage in the retina is associated with a number of serious ocular diseases including vision loss. Studies proposed in this application are designed to enhance our understanding of molecular pathways that control the spatial organization of retinal vascular system and therefore aid the development of therapeutic methods to repair retinal blood vessels.