Wednesday, January 15, 2025
1/15/2025
An excess of circulating lipids in conjunction with dysregulated retinal de novo lipogenesis results in retinal lipotoxicity which can lead to retinal inflammation and apoptosis contributing to the pathogenesis of diabetic retinopathy (DR). The nuclear retinoid X receptor (RXR), shown to be diminished in human and mouse diabetic retinas, is of particular interest for therapeutic intervention due to its binding and activation of PPAR and LXR that regulate the expressions of lipid metabolism-associated and inflammation-related genes. Recently we synthesized two small molecules, the RXR agonists (rexinoids) UAB30 and UAB126 which demonstrated marked efficacy in reducing DR progression when given systemically; however these agents reduced hyperglycemia and thus the beneficial effect of rexinoids on DR could be directly due to improvement in diabetes management. In the proposed studies, we directed our efforts towards developing retinal delivery of rexinoids to remove the confounding effect on glucose regulation and establish whether this targeted delivery could beneficially impact retinal lipid metabolism and reduce retinal inflammation directly. Our overarching hypothesis is that intravitreal (IVT) delivery of rexinoids as sustainable released microparticles (UAB126-MP and UAB30-MP) will activate RXR, provide a long-term therapy for DR, and enhance the pool of RXR homodimers available to partner with the PPARs and LXRs to both prevent and reverse DR. Therefore, we propose that rexinoids act through the stabilization of the RXR/PPAR and RXR/LXR complexes leading to the normalization of lipid metabolism and correction of neurovascular defects typically seen in DR. We will test our hypothesis using IVT formulations of UAB126 and UAB30 and two diabetic mouse models, as well as ex vivo retinal models, primary human retinal microvascular endothelial and human retinal pigment epithelial cell cultures, and a diverse set of molecular biological applications. In Aim#1, we proposed to determine the physiological effect of RXR-based therapy in diabetic retinas by assessing the pharmacokinetics of UAB126- MP and UAB30-MP and the therapeutic impact of IVT rexinoids to prevent and reverse DR. In Aim#2, we will investigate the cellular mechanism of RXR-based therapy by examining the control of RXR on retinal lipid profile and reveal the retinal cell type most vulnerable to RXR deficiency in diabetes. In Aim#3, we will focus on molecular mechanisms of RXR-based therapy by investigating the requirement of PPAR and/or LXR as binding partners of RXR in the retina and the gene expression network regulated by PPAR and LXR responsive elements as consequences of IVT rexinoid delivery. This proposed study is highly innovative and has marked translational significance by targeting retinal lipotoxicity and retinal inflammation and could be tested not only as a monotherapy but also in combination with existing therapies for DR. Our interdisciplinary team has expertise in drug discovery, ocular drug delivery, cell biology, biochemistry, and metabolism of the diabetic retina and thus we have all the tools necessary to successfully accomplish this translational research.
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