Spatial cues for retinal angiogenesis

视网膜血管生成的空间线索

• 批准号: 7903883
• 负责人: Guo-Hua Fong
• 金额: $ 50.06万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7903883
• 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; Gray unit of radiation dose; Growth; Histocompatibility Testing; Hydroxylation; Hypoxia; Hypoxia Inducible Factor; Inner Plexiform Layer; Lead; Location; Mediating; Membrane; Methods; 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; Vascular Endothelial Cell; 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; hypoxia inducible factor 1; multicatalytic endopeptidase complex; new growth; novel; outer plexiform layer; overexpression; paracrine; prevent; public health relevance; repaired; retina blood vessel structure; retinal angiogenesis; retinal damage; therapeutic development; transcription factor; vascular bed; vasculogenesis

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.

描述（由申请人提供）：视网膜脉管系统容易受损，导致严重的眼部疾病，包括视力丧失。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由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充当空间线索来确定视网膜中血管生长的方向和位置。这些研究将针对三个具体目标进行。目标 1. 研究脯氨酰羟化酶结构域蛋白在控制视网膜血管模式形成中的作用。 PHD 负向调节缺氧诱导因子 (HIF) 的丰度，后者对于血管生成至关重要。我们假设组织微环境中的 PHD 活性水平决定了其附近血管生长的活性和方向性，并将通过生成包含 PHD 缺陷或过度表达的微组织域的嵌合视网膜来检验这一假设。目标 2. 确定微组织域中的 HIF-1 α 积累是否控制附近组织中血管生长的位置和方向。目标 3. 探索 VEGFR-1 在定义血管间距离中的作用。 VEGFR-1 由内皮细胞产生，并与 VEGF-A（缺氧诱导的关键血管生成分子）形成紧密复合物。我们认为 VEGF-A/VEGFR-1 相互作用会减少 VEGFR-1 表达源附近的生物利用度 VEGF-A，因此不允许在距现有微血管一定距离内生长更多微血管。这一假设将通过创建含有过度表达 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进行检验。这些研究的目的是促进开发旨在修复受损视网膜血管床的有效疗法，并且与国家眼科研究所（NEI）的承诺高度一致。公众健康相关性：视网膜血管损伤与许多严重的眼部疾病（包括视力丧失）有关。本申请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。