The influence of LRG1 (leucine-rich alpha-2-glycoprotein-1) on structure and function of ocular blood vessels

LRG1（富含亮氨酸的α-2-糖蛋白-1）对眼部血管结构和功能的影响

• 批准号: 277082201
• 负责人: Dr. Alexandra Höh
• 金额: --
• 依托单位: Institute of Ophthalmology
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2016-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/277082201?language=en
• 关键词: influence; LRG1; leucine; rich; alpha

Vascular disorders of the retina, such as diabetic retinopathy and exudative age-related macular degeneration, are among the most frequent causes of blindness in the western industrialized nations. In these conditions, anomalies in angiogenic signalling lead to the formation of new blood vessels and/or changes to the structure of preexisting vessels causing leakage of fluid into the surrounding tissues and haemorrhage. Many mechanisms that are involved in the coordination of the growth of neovascular blood vessels, like the interaction of intrinsic molecular cues in endothelial cells and signals derived from the surrounding tissues, are still unknown. Yet many of the known molecular drivers of pathological angiogenesis are those that also regulate normal vessel growth in developmental angiogenesis. This paradox highlights the context-dependent nature of neovascularisation and the need to understand the complexity of localized signalling patterns that lead to different angiogenic outcomes. In a recent study the host laboratory reported the discovery of a new pro-angiogenic secreted glycoprotein: leucine-rich alpha-2-glycoprotein-1 (LRG1). LRG1 promotes pathogenic angiogenesis by modifying transforming growth factor-beta (TGFbeta) signalling and it was further shown that LRG1 operates independently of the prototypic vascular endothelial growth factor (VEGF) signalling axis. The aim of the project outlined in this application is to investigate the role of LRG1 with regard to ocular vascular structure and function. We will therefore investigate, using ocular models of pathogenic angiogenesis, namely oxygen induced retinopathy, laser-induced choroidal neovascularisation (CNV), spontaneous CNV mouse and the corneal abrasion model, whether VEGF in the presence of LRG1 promotes pathogenic and disorganised vessel growth, while mediating patterned physiological vessel growth in its absence. We will undertake a detailed examination of vascular structure and function of neovessels in these models induced either in LRG1 knockout mice or in wild type mice following LRG1 blockade with a blocking antibody. We will determine whether loss of LRG1 reduces the number of neovascular lesions and whether it allows normalisation of vessel structure and function. This study will also provide further evidence of the potential clinical utility of a therapeutic antibody targeting of LRG1.

视网膜血管疾病，如糖尿病视网膜病变和渗出性年龄相关性黄斑变性，是西方工业化国家最常见的致盲原因之一。在这些病症中，血管生成信号传导的异常导致新血管的形成和/或预先存在的血管的结构的改变，从而导致液体渗漏到周围组织中和出血。参与新生血管生长协调的许多机制，例如内皮细胞中内在分子线索与来自周围组织的信号的相互作用，仍然未知。然而，许多已知的病理性血管生成的分子驱动因子是在发育性血管生成中也调节正常血管生长的那些分子。这种矛盾突出了新血管形成的背景依赖性，以及了解导致不同血管生成结果的局部信号模式的复杂性的必要性。在最近的一项研究中，宿主实验室报告发现了一种新的促血管生成分泌糖蛋白：富含亮氨酸的α-2-糖蛋白-1（LRG 1）。LRG 1通过修饰转化生长因子-β（TGF β）信号传导促进致病性血管生成，并且进一步显示LRG 1独立于原型血管内皮生长因子（VEGF）信号传导轴运作。本申请中概述的项目的目的是研究LRG 1在眼血管结构和功能方面的作用。因此，我们将使用致病性血管生成的眼部模型，即氧诱导的视网膜病变、激光诱导的脉络膜新生血管形成（CNV）、自发性CNV小鼠和角膜擦伤模型，研究VEGF在LRG 1存在下是否促进致病性和无序的血管生长，同时在其不存在下介导图案化的生理血管生长。我们将进行详细的检查血管结构和功能的新生血管在这些模型中诱导无论是在LRG 1基因敲除小鼠或野生型小鼠后，LRG 1阻断抗体。我们将确定LRG 1的缺失是否会减少新生血管病变的数量，以及它是否允许血管结构和功能的正常化。本研究还将提供靶向LRG 1的治疗性抗体的潜在临床效用的进一步证据。