Retinal Microglia and Angiogenesis

视网膜小胶质细胞和血管生成

• 批准号: 8461948
• 负责人: Richard A. Lang
• 金额: $ 36.34万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8461948
• 关键词: Age related macular degeneration; Attention; Biological Assay; Blood Vessels; Cells; Choroidal Neovascularization; Color; Cues; Cyclic GMP; Data; Development; Diabetic Retinopathy; Disease; Eye; Filopodia; Genetic; Growth; Growth Factor; Home environment; Homeostasis; Isolectin; Label; Ligands; Mediating; Microglia; Modeling; Mus; Myeloid Cells; Nature; Neuroglia; Pathway interactions; Pattern; Play; Production; Publishing; Regulation; Retina; Retinal; Retinopathy of Prematurity; Role; Schedule; Signal Transduction; Source; Structure; Suggestion; Testing; Up-Regulation; Vascular Diseases; Vascular Endothelial Growth Factors; Vascular System; Vision; Work; angiogenesis; autocrine; base; in vivo; inhibitor/antagonist; macrophage; notch protein; postnatal; reconstruction; response; retinal angiogenesis; spatial relationship; vessel regression

DESCRIPTION (provided by applicant): The vascular system plays a fundamentally important role in development, homeostasis and disease. With examples of scheduled vascular regression (the hyaloid vessels) and in the mouse, postnatal angiogenesis (in the retina), the eye is an excellent structure in which to study vascular development. In this application, we propose to study to role of retinal microglia, a type of myeloid cell, in the regulation of retinal angiogenesis. Based on published and preliminary studies, we propose the hypothesis that Retinal microglia regulate vascular pattern by producing VEGF and, via Wnts and possibly Notch, the VEGF inhibitor Flt1. We propose three aims to investigate this hypothesis: (1) to determine whether microglial or Muller glial VEGF mediates attractive guidance for deep layer retinal angiogenesis. Published work shows that Muller glia makes VEGF and our Preliminary Studies show that microglia also do. These are two possible sources of VEGF that might act as an attractive guidance cues for descending angiogenic sprouts. (2) To determine whether the non-canonical Wnt-Flt1 response of microglia is the Wnt-cGMP/Ca2+ pathway. Our Preliminary Studies suggest that the non-canonical Wnt-cGMP/Ca2+ pathway are involved in the production of Flt1 by microglia. We will further assess these using pharmacological inhibitors in a culture assay and by assessing the in vivo consequences of genetic deletion of pathway components. (3) To determine whether a microglial Notch response up-regulates Flt1 and integrates with the Wnt pathway. Published work and Preliminary Studies show that both VECs and microglia show Notch-dependent up-regulation of Flt1. This raises the possibility that when angiogenic tip cells (that express the Notch ligand Dll4 in the deep vascular layer), make contact with microglia, there is an up-regulation of Flt1. Given that Wnts also regulate Flt1 expression, it also suggests that the Wnt and Notch pathways must be integrated. These studies are important in uncovering basic mechanisms by which angiogenesis is normally regulated and as a result, uncovering new ways in which blood vessel growth and regression might be regulated therapeutically. In particular, this work has implications for the vision-compromising ailments diabetic retinopathy, age-related macular degeneration and retinopathy of prematurity.

描述（由申请人提供）：血管系统在发育，体内平衡和疾病中起着重要的重要作用。以计划的血管回归（透明血管）和小鼠的例子为例，在产后血管生成（在视网膜中），眼睛是研究血管发育的出色结构。在此应用中，我们建议研究视网膜细胞的视网膜小胶质细胞的作用 血管生成。基于已发表的初步研究，我们提出了以下假设：视网膜小胶质细胞通过产生VEGF以及通过WNT和可能的Notch调节VEGF抑制剂FLT1来调节血管模式。我们提出了三个目的旨在研究这一假设：（1）确定小胶质细胞和muller glial vegf是否介导了深层视网膜血管生成的有吸引力的指导。已发表的工作表明，穆勒神经胶质构成VEGF，我们的初步研究表明，小胶质细胞也可以。这是VEGF的两个可能来源，可以充当降序血管生成的有吸引力的指导线索。 （2）确定小胶质细胞的非经典WNT-FLT1反应是否是Wnt-CGMP/Ca2+途径。我们的初步研究表明，非典型的Wnt-CGMP/Ca2+途径参与小胶质细胞的FLT1的产生。我们将使用药理学抑制剂在培养测定中进一步评估这些抑制剂，并通过评估途径成分遗传缺失的体内后果。 （3）确定小胶质细胞响应是否上调FLT1并与Wnt途径集成。已发表的工作和初步研究表明，VEC和小胶质细胞都表现出Notch依赖性FLT1的上调。这增加了一种可能性，即当血管生成尖端细胞（在深血管层中表达缺口配体DLL4），与小胶质细胞接触时，FLT1的上调就会上调。鉴于Wnt还调节了FLT1表达，因此还表明必须集成Wnt和Notch途径。这些研究在发现通常受到血管生成的基本机制方面很重要，因此，发现血管生长和退化可能会受到治疗的新方法。特别是，这项工作对视觉促进性疾病糖尿病性视网膜病，与年龄相关的黄斑变性和早产性视网膜病具有影响。