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

视网膜血管疾病，如糖尿病视网膜病变和渗出性老年性黄斑变性，是西方工业化国家最常见的致盲原因。在这些情况下，血管生成信号的异常导致新血管的形成和/或原有血管结构的改变，导致液体渗漏到周围组织和出血。许多参与新血管生长协调的机制，如内皮细胞的内在分子信号和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素也调节发育性血管生成中的正常血管生长。这一悖论强调了新生血管形成的环境依赖性，以及理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 （LRG1）。LRG1通过调节转化生长因子- β (tgf - β)信号通路促进致病性血管生成，研究进一步表明，LRG1独立于原型血管内皮生长因子（VEGF）信号轴发挥作用。本项目的目的是研究LRG1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，即氧诱导视网膜病变、激光诱导脉络膜新生血管（CNV）、自发CNV小鼠和角膜磨损模型，研究LRG1存在时VEGF是否促进致病性和无组织血管生长，同时在LRG1不存在时介导有模式的生理性血管生长。我们将在LRG1敲除小鼠或LRG1阻断抗体后的野生型小鼠中，对这些模型中新生血管的血管结构和功能进行详细检查。我们将确定LRG1的缺失是否会减少新血管病变的数量，以及它是否允许血管结构和功能的正常化。这项研究还将进一步证明针对LRG1的治疗性抗体的潜在临床应用。

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.