Hypoxia mediated alternative splicing of the erythropoietin receptor (EPOR) in the retina

Abstract

Erythropoietin (EPO) is a haematopoietic glycoprotein that is involved in erythropoiesis in the haematopoietic tissues and tissue protection in non-haematopoietic tissues. EPO mediates its signals by binding to its receptor, the erythropoietin receptor (EPOR). EPO has been investigated as a promising therapeutic agent in ischaemic retinopathies and glaucoma. Alternative splicing is one the most important post-transcriptional events that is responsible for generating vast protein diversity from a relatively limited number of genes, allowing the synthesis of several structurally and functionally distinct protein isofonns. In erythroid cells alternative splicing of EPOR generates three transcripts; full length (EPOR-F), soluble (EPOR-S) and truncated (EPOR-T). The full length contains the entire coding region of EPOR, while the soluble only encodes the region coding for extracellular domain resulting in the receptor being secreted in the extracellular space and the truncated variant lacks a part of the region coding for the cytoplasmic domain and act as a dominant negative regulator of EPO-EPOR mediated signals for cell survival. In this study, all three EPOR splice variants are expressed in the normal retina and EPOR-F is present in all three retinal cell layers. EPOR- T is shown to be upregulated in the mouse model of oxygen induced retinopathy (OIR) and in-vivo model of hypoxia. The upregulation of EPOR- T was associated with hypoxia mediated cell death. This hypoxia mediated upregulation of EPOR - T is abolished in presence of exogenous EPO and hypoxia mediated cell death is abolished upon knockdown of EPOR - T. The role of EPOR -Tin ischaemic cell death presents a novel therapeutic target in both retinal and non-ocular tissues.EThOS - Electronic Theses Online ServiceGBUnited Kingdo