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

• Applicant: Dr. Alexandra Höh
• Subject Area: Ophthalmology
• Term: from 2015 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 277082201

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.

• DFG Programme: Research Fellowships
• International Connection: United Kingdom
• Host: Professor John Greenwood, Ph.D.