Hyperoxia and enhancing efferocytosis in the eye - PROJECT ABSTRACT – Hyperoxia and enhancing efferocytosis in the eye The remarkable advances in supplemental oxygen provision have been a huge benefit for preterm babies during a critical phase of their development ex utero, but also have an unintended consequence of developing retinopathy of prematurity (ROP). ROP is a leading cause of childhood blindness in the United States and worldwide, with a high risk of vision loss or permanent impairment in severe refractory cases. During the disease course of ROP, many retinal neuronal cells undergo cell death, which necessitates the clearance of the cell debris and corpses. The recognition and removal of dying cells via the process of efferocytosis not only removes the debris but also promotes tissue regeneration and healing (including angiogenesis). Interestingly, specific glial cells within the retina express phagocytic receptors and other machinery that can promote efferocytosis. We have previously designed and validated chimeric efferocytosis (CHEF) receptors, which improve the efferocytic capacity of phagocytes. Our recent preliminary data in a mouse model of oxygen-induced retinopathy (OIR) suggest that CHEF receptor expressed in the microglia can beneficially influence the OIR outcomes. This R21 application aims to investigate the interplay between debris/dying cell clearance by specific phagocytes in the retina, and the possibility of improving retinal tissue healing in OIR. Using recent knowledge on improving efferocytic clearance in vivo and transgenic mouse models developed in our laboratory, we will ask two fundamental questions in this exploratory proposal. In Aim 1, we will address whether cell-type specific expression of the CHEF receptor BELMO in Müller cells versus microglia will improve the outcomes of OIR, coupled with mechanistic studies. In Aim 2, we will test a preclinical approach to express the CHEF receptor TELMO (via mRNA based nanoparticle), coupled with studies using TELMO transgenic mice. Collectively, we expect the studies via this R21 to provide exciting new insights and form the basis for exploring new avenues targeting efferocytic pathways during ROP.
