Vision Research Lab
Principal Investigator: Dr. Priya Narayanan
Major focus of our laboratory is to identify therapeutic targets for vision disorders by understanding the mechanisms regulating neurovascular damage in the retina. Retinal neurovascular injury is a major cause of vision impairment in disorders such as diabetic retinopathy, optic neuritis and retinopathy of prematurity, affecting both children and adults worldwide. The major goal of our current studies is to identify the molecular pathways of retinal Spermine Oxidase (SMOX, an important enzyme in polyamine catabolic pathway) regulation and its therapeutic potential under pathological conditions in the retina.
Project 1: Spermine oxidase as a therapeutic target neurodegeneration in diabetic retinopathy. Diabetic retinopathy (DR) is a significant public health issue and the leading cause of vision loss in working aged adults in the US. The available therapies so far are focused on the later stage of diabetes and have adverse side effects. Hence there is a great need for therapies for early stages of DR. Recent studies have shown that retinal neurodegeneration is an early event in DR progression; however, the mechanisms underlying this process are poorly understood. Our goal is to contribute to the treatment of DR, by defining the specific role of Spermine Oxidase (SMOX) in causing neuronal injury and RGC death in the diabetic retina and demonstrating its potential as a therapeutic target for DR treatment. Studies from our laboratory using diabetic mouse models have shown that expression of SMOX and its downstream byproduct acrolein are increased in diabetic retina. Treatment with SMOX inhibitor, MDL 72527 improved diabetes-induced decrease in retinal structure and function. Studies are in progress to identify the mechanisms involved in SMOX-induced neurodegeneration in diabetic retina. The question we are addressing now is the SMOX regulated molecular mechanisms involved in the retinal damage and dysfunction in diabetic retina. Using the transgenic mouse model overexpressing SMOX in retinal neurons, we are investigating SMOX regulated mechanisms of neurodegeneration in diabetic retina and the therapeutic potential of SMOX inhibition in the prevention and treatment of diabetic retinopathy. These studies have already supported by an NIH R01 from the National Eye Institute.
Project 2: Mechanisms of neurovascular damage in ischemic retinopathy: Role of spermine oxidase. Neuronal and vascular damage to the retina are the major causes of vision loss in diseases such as diabetic retinopathy, retinopathy of prematurity and glaucoma. We have been investigating the impact of polyamine oxidase in mediating retinal neurovascular damage using different retinal injury models. Studies using the Oxygen Induced Retinopathy (OIR) model, we have shown that arginase and its downstream signaling partner, polyamine oxidase are involved in mediating hyperoxia-induced neuronal damage and dysfunction (Narayanan et al 2014). Further studies in our laboratory have shown that treatment with polyamine oxidase inhibitor improved neurovascular damage and glial activation in OIR retina (Patel et al 2016). We also identified the involvement of activated microglia in mediating neurovascular damage to the retina. Ongoing studies in our laboratory are investigating the mechanisms by which microglia derived microparticles mediate retinal neurovascular damage and dysfunction in ischemic retinopathy models. Utilizing the models of ischemic retinopathy (OIR and Ischemia/Reperfusion injury) and NMDA induced-retinal excitotoxicity and SMOX transgenic mice, we are addressing the mechanisms by which neurons, glia, and vasculature interact in mediating visual dysfunction.
Project 3: Role of arginase/polyamine signaling in multiple sclerosis mediated retinal neuronal damage and visual dysfunction. Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system characterized by demyelination, inflammatory responses, and neurodegeneration. Visual dysfunction, resulting from optic neuritis is the first and one of the most common clinical manifestations of MS and can lead to temporary or permanent vision loss. Current medications available for MS are only partially effective as they specifically target the inflammatory phase, but not the neurodegenerative phase, and therefore have limited effects on long-term disability. Thus, there is a great need for identifying new agents that target both inflammatory and neurodegenerative phases of MS and optic neuritis. Considering the major regulatory role of arginase in nitric oxide signaling, and the mitochondrial localization of arginase 2 (A2), we hypothesize that A2 plays a crucial role in the neurodegeneration/visual dysfunction associated with MS. Demonstrating the involvement of arginase and its downstream signaling partner, polyamine oxidase would be of great importance in identifying new therapeutic targets for treating vision problems in MS patients. Our laboratory has developed the EAE mouse model for studying MS associated neurodegeneration in the retina. We are currently investigating the changes in arginase and SMOX signaling and retinal structural and functional studies. These studies have been supported by pilot awards from National Multiple Sclerosis Society and Augusta University Culver Vision Discovery Institute. Our studies will evaluate the potential therapeutic benefits of targeting arginase/polyamine signaling pathways for treating MS patients in reducing vision problems.
5 R01 EY028569; 05/01/2018 – 04/30/2023; National Eye Institute; Mechanisms of neurodegeneration in diabetic retinopathy: Role of spermine oxidase; Role: PI
5I01BX001233-01;10/01/2015 – 09/30/2019; VA Merit Review Award; PI: Caldwell; Title: Mechanisms of Traumatic Retinopathy: Role of Arginase; Role: Co-I
PP-1606-08778;11/1/2016-1/31/2018; National Multiple Sclerosis Society; Role of arginase in Multiple Sclerosis Mediated Retinal Neuronal Injury; Role: PI
ESA00036; Extramural Success Award (Augusta University); 10/1/2017- 4/30/2018; Title: Mechanisms of neurodegeneration in diabetic retinopathy: Role of Spermine Oxidase Role: PI
5 R01 EY011766-15; 03/01/2013 – 02/28/2018; NIH/National Eye Institute; Title: PI: Caldwell; Cellular Mechanisms of Retinopathy: Role of Arginase; Role: Co-I
11SDG7440088; 07/01/2011 – 06/30/2015; American Heart Association – Scientist Development Grant; Title: Role of neuronal arginase on vascular protection during ischemic retinopathy; Role: PI