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.