The Augusta University Vision Research Laboratory focuses on identifying therapeutic targets for ocular diseases such as diabetic retinopathy, retinopathy of prematurity, and optic neuritis, diseases which share a common feature of neurovascular damage in the retina. Both in vivo and in vitro approaches are employed to investigate the role of arginase/polyamine pathway in retinal neurovascular injury. We have previously shown that arginase, the urea cycle enzyme, regulates neuro-glial injury and retinal function in models of retinal neurodegeneration. Current projects explore the cellular and molecular mechanisms by which retinal arginase signaling and its downstream signaling partner, polyamine oxidase, are involved in neuro-vascular protection during retinal injuries. Experiments using knockout mice, cultured cells, and pharmacological inhibitors in ocular disease models have significant implications in the development of new therapies for vision problems.
Role of arginase signaling in multiple sclerosis associated neuronal injury
Using animal models, this study examines the involvement of arginase and its downstream
signaling partners in Retinal Ganglion Cells loss. Studies have shown that multiple
sclerosis patients develop optic neuritis characterized by thinning of nerve fiber
layer, loss of RGC, and loss of inner retinal function, resulting in visual dysfunction,
one of the most common clinical manifestations of MS. We hypothesize that activation
of arginase pathway causes neuronal injury in the MS retina. Principal Investigator, supported by Augusta University Culver Vision Discovery Institute
Role of neuronal arginase on vascular protection during ischemic retinopathy
A study on the impact of neuronal survival on vascular protection under ischemic conditions
in the retina. Our central hypothesis is that during retinal ischemia, arginase activity
increases resulting in altered nitric oxide signaling and increased polyamine oxidation,
leading to the generation of reactive nitrogen species, hydrogen peroxide, and reactive
aldehydes, causing neurodegeneration. This further leads to endothelial cell death
either by the release of toxic soluble factors or due to the lack of trophic support
from degenerating neurons resulting in vascular injury. Our recent studies have shown
Arginase 2 functions to reduce neuronal death during hyperoxia through the regulation
of polyamine metabolism. Principal Investigator, supported by American Heart Association
Cellular mechanisms of retinopathy: Role of arginase
An investigation into the role of Arg2 in neuronal and capillary degeneration resulting
from retinal ischemia/reperfusion injury. Excessive activity of the urea cycle enzyme
arginase has been implicated in a variety of cardiovascular and neurodegenerative
diseases. Preliminary data from this study show that deletion of arginase 2 or inhibition
of arginase activity significantly reduces ganglion cell death in the I/R retina.
We are currently focusing on the signaling mechanisms by which arginase blockade mediates
neuro-vascular protection during I/R injury. Co-Investigator, supported by National Eye Institute
Patel C,Narayanan SP, Zhang W, Xu Z, Sukumari-Ramesh S, Dhandapani KM, Caldwell RW, Caldwell RB. "Activation of endothelin system mediates pathological angiogenesis during ischemic retinopathy."American Journal of Pathology 2014. Nov; 184(11):3040-51. PMCID: PMC4215027
Narayanan SP, Xu Z, Putluri N, Sreekumar A, Lemtalsi T, Caldwell RW, Caldwell RB. "Arginase 2 deficiency reduces hyperoxia-mediated retinal neurodegeneration through the regulation of polyamine metabolism." Cell Death Disease 2014 Feb 20; 5:e1075. PMCID: PMC3944241.
S. P. Narayanan, M. Rojas, J. Suwanpradid, H.A. Toque, R. W. Caldwell, R.B. Caldwell. "Arginase in Retinopathy." Progress in Retinal and Eye Research 2013. Sep;36:260-80PMCID: PMC3759622
Yokota H,Narayanan SP, Zhang W, Liu H, Rojas M, Xu Z, Lemtalsi T, Nagaoka T, Yoshida A, Brooks SE, Caldwell RW, Caldwell RB" Neuroprotection from retinal ischemia/reperfusion injury by NOX2 NADPH oxidase deletion." Investigative Ophthalmic Visual Science 2011 52(11):8123-31.PMCID: PMC3208002
Narayanan, SP, Suwanpradid, J, Saul, A, Xu, Z,Caldwell, RW and Caldwell, RB "Deletion of Arginase 2 reduces neurodegeneration and improves retinal function in a mouse model of oxygen induced retinopathy." PLoS<ONE62011.(7):e22460. PMCID:PMC3141070