BLR&D Research Career Scientist Award Application

Project Summary: The goal of Dr. Caldwell?s current VA research is to delineate the molecular mechanisms that lead to trauma-induced retinal neuronal and vascular injury and identify novel strategies to prevent or reverse the damage and preserve vision. The lack of understanding of the detailed molecular mechanisms by which ocular trauma damages the retinal neurons and vascular cells represents a critical knowledge gap in developing effective therapies. Therefore, the goal of this research is to define these mechanisms and identify innovative approaches to prevent such damage, improve functional outcomes and reduce the risk of blindness to veterans returning from the battlefield. Dr. Caldwell?s group has shown that ischemia or trauma-induced activation of the mitochondrial, ureohydrolase enzyme arginase 2 causes microglia/macrophage activation and neurovascular degeneration by increasing oxidative stress and inflammation. Overactive arginase can increase oxidative stress by 1) decreasing the L-arginine supply needed by nitric oxide synthase (NOS) to produce NO, thereby causing NOS to become uncoupled and produce superoxide that reacts with NO to form the toxic oxidant peroxynitrite and/or 2) causing excessive activation of the ornithine-polyamine pathway, thereby leading to polyamine oxidation and production of toxic oxidants. Thus, overactive arginase 2 could cause neurovascular damage by uncoupling NOS and/or activating polyamine oxidase. Their studies are developing this concept in two specific aims. Aim 1 is testing the hypothesis that traumatic retinal injury is mediated by arginase-induced uncoupling of NOS and/or altered polyamine metabolism. These studies are determining the effects of arginase knockdown on inflammation, neurovascular degeneration and retinal function in mouse models of traumatic retinal injury. The studies are examining the protective effects of arginase deletion on neurovascular damage in relation to NOS function and polyamine metabolism, expression of polyamine oxidase enzymes and their activity in producing ROS. The studies are characterizing retinal structure and function by in vivo imaging and electroretinography, respectively. The results to date indicate that arginase 2 deletion limits inflammation and mitigates neurovascular damage/dysfunction by normalizing NOS function and limiting oxidative stress. Aim 2 studies seek to develop a new therapy for prevention and treatment of traumatic retinal neurovascular injury. These studies are comparing the treatment efficacy and safety of inhibiting arginase signaling and/or polyamine metabolism in limiting or preventing inflammation and retinal neurovascular injury in models of traumatic retinal injury as explained for Aim 1. The outcomes include validation of the arginase/polyamine pathway as a novel target for therapeutic intervention to attenuate oxidative stress, inflammation and neurovascular degeneration and promote healthy repair following traumatic retinal injury. This work will serve as a basis for development of novel therapeutic agents to treat optic neuropathy. In view of the high incidence of traumatic ocular neuropathy following battlefield injury, this project is highly relevant to the mission of VA and to the health and well-being of veterans.