Spatial cues for retinal angiogenesis

视网膜血管生成的空间线索

基本信息

批准号：
8518334
负责人：
Guo-Hua Fong
金额：
$ 47.1万
依托单位：
UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-01 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8518334
关键词：
Affect Angiogenesis Inhibitors Angiogenic Factor Architecture Bioavailable Blindness Blood Vessels Blood capillaries Complex Cues Cytoplasmic Tail Development Diabetic Retinopathy Disease Endothelial Cells Ensure Figs - dietary Ganglion Cell Layer Growth Histocompatibility Testing Hydroxylation Hypoxia Hypoxia Inducible Factor Inner Plexiform Layer Lead Location Mediating Membrane Methods Mission Molecular National Eye Institute Nerve Fibers Oxygen Pathway interactions Pattern Pattern Formation Polyubiquitination Positioning Attribute Process Procollagen-Proline Dioxygenase Protein Isoforms Proteins Regulation Retina Retinal Retinopathy of Prematurity Role Shapes Signal Pathway Signal Transduction Source Specific qualifier value Structure Tertiary Protein Structure Testing Time Tissues Translating Transmembrane Domain Vascular Endothelial Cell Vascular Endothelial Growth Factor Receptor Vascular Endothelial Growth Factor Receptor-1 Vascular Endothelial Growth Factor Receptor-2 Vascular Endothelial Growth Factors Vascular System Vascularization angiogenesis bHLH-PAS factor HLF capillary density design effective therapy multicatalytic endopeptidase complex novel outer plexiform layer overexpression paracrine prevent repaired retina blood vessel structure retinal angiogenesis retinal damage therapeutic development transcription factor vascular bed vasculogenesis

项目摘要

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-la accumulation in a micro tissue domain controls the position and direction of vascular growth in nearby tissues. Aim 3. Explore the role of VEGFR-l in defining vessel to vessel distances. VEGFR-l 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-l 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 consistent with the mission of the National Eye Institute (NEI).

视网膜脉管系统容易受到损害，导致严重的眼部疾病，包括视力丧失。尽管正在探讨血管生成疗法作为潜在疗法，但一个重大障碍是我们无法控制由血管生成因子诱导的血管网络的三维组织，以确保药理诱导的视网膜血管的正确功能。因此，我们的长期目标是阐明控制视网膜血管床的空间组织的机制，尤其是研究缺氧信号传导途径的成分如何作为确定视网膜血管生长方向和位置的空间提示。这些研究将以三个具体目标进行。目标1。研究丙酰羟化酶结构蛋白在控制视网膜血管模式形成中的作用。 PHD对低氧诱导因子（HIF）的丰度负调节，后者对于血管生成至关重要。我们假设组织微环境中的PHD活性水平决定其附近血管生长的活性和方向性，并通过产生包含具有PHD缺乏或过表达的微组织结构域的嵌合视网膜来检验该假设。 AIM 2。确定HIF-LA在微组织结构域中积累是否控制附近组织中血管生长的位置和方向。 AIM 3。探索VEGFR-L在将血管定义为容器距离方面的作用。 VEGFR-L由内皮细胞产生，并与VEGF-A形成紧密复合物，VEGF-A是由缺氧诱导的关键血管生成分子。我们建议VEGF-A/VEGFR-1相互作用在VEGFR-L表达来源附近降低了可生物可利用的VEGF-A，因此不允许在与现有微血管一定距离内的更多微量花序的生长。该假设将通过创建包含过表达VEGFR-1的微组织结构域并评估此类组织附近的血管密度的嵌合视网膜来检验。这些研究的目的是促进旨在修复损坏的视网膜血管床的有效疗法的开发，并且与国家眼科研究所（NEI）的任务高度一致。