Multi OMICS Approach Towards Understanding the Pathogenesis of Retinopathy of Prematurity

Abstract

Retinopathy of prematurity (ROP) is a complex vaso-proliferative eye condition that affects newlineprematurely born infants worldwide. It has a high prevalence of 24-47% in India. Despite timely newlineinterventions, a proportion of babies progress to severe stages of the disease. The overall molecular newlineetiology leading to ROP pathogenesis is not well known. newlineEarlier research from our group revealed an interplay of microglia and MMPs in ROP newlinepathogenesis. In the present study, we observed that tear MMP activation occurred prior to the newlinedevelopment of severe ROP and thus could serve as a potential marker for early detection. Under newlinehypoxic stress, activated microglial cells in the retina secreted MMP9, which led to the newlinedownregulation of Opticin. Further, the inhibition of the MMP activity by doxycycline and EDTA newlinerescued Opticin degradation mediated by NOTCH1, ERK1 and WNT signaling. These results newlineconfirmed that microglia-mediated inflammation degraded ECM proteins and led to angiogenesis newlinein ROP eyes. Our whole-exome analysis on ROP exhibited novel mutations in genes involved in newlinemetalloendopeptidase, WNT pathways and metabolic pathways (fatty acid, arachidonic acid). newlineGlobal gene expressions in these patients further confirmed the upregulation of angiogenic genes newlinewith concurrent downregulation of the WNT regulatory genes and anti-apoptotic NK cells newlineregulatory genes in ROP. Likewise, metabolomic analysis of ROP vitreous samples indicated an newlineincrease in amino acid, lipids and bioenergetics derived metabolites leading to increased cell death, newlineinflammation and abnormal angiogenesis in the retina. Our multi-OMICS approach demonstrated newlinethe potential involvement of several signaling pathways, including WNT, MAPK, NOTCH1, and newlinethe metabolism of amino acids and lipids in ROP pathogenesis. newline