Spatial cues for retinal angiogenesis

描述（申请人提供）：视网膜血管容易受损，导致包括视力丧失在内的严重眼部疾病。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，我们的长期目标是揭示控制视网膜血管床空间组织的机制，特别是研究缺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。研究脯氨酸羟化酶结构域蛋白在控制视网膜血管模式形成中的作用。博士学位负向调节缺氧诱导因子（hif）的丰度，后者是血管生成所必需的。我们假设组织微环境中的PHD活性水平决定了其附近血管生长的活性和方向性，并将通过生成含有PHD缺乏或过表达的微组织结构域的嵌合视网膜来验证这一假设。目标2。确定HIF-1 α在微观组织结构域中的积累是否控制了附近组织中血管生长的位置和方向。目标3。探讨VEGFR-1在确定血管间距离中的作用。VEGFR-1由内皮细胞产生，与缺氧诱导的关键血管生成分子VEGF-A形成紧密复合物。我们认为VEGF-A/VEGFR-1的相互作用减少了VEGFR-1表达源附近的生物可用性VEGF-A，因此不允许在距离现有微血管一定距离内生长更多的微血管。这一假设将通过制造嵌合视网膜来验证，嵌合视网膜包含过表达的微组织结构域，VEGFR-1，并评估这些组织附近的血管密度。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发展，并与美国国家眼科研究所（NEI）的使命高度一致。公共卫生相关性：视网膜血管损伤与包括视力丧失在内的许多严重眼部疾病有关。本应用中提出的研究旨在增强我们对控制视网膜血管系统空间组织的分子途径的理解，从而有助于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.