Steven F. Abcouwer, Ph.D.
Research
Dr. Abcouwer's research is aimed at understanding various machanisms/processes that contribute to the development of diabetic retinopathy, including neural degeneration, vascular dysfunction, and the function and activation of immune cells. He serves on the Juvenile Diabetes Research Foundation Diabetic Retinopathy Center leadership team. He is Co-Principal Investigator of the Preclinical Interventions Study (Project 2) of the Center along with Dr. David Antonetti. Together, they are examining the potential of various FDA-approved drugs to inhibit neurodegeneration and vascular dysfunction caused by retinal ischemia-reperfusion injury (IR), as well as diabetic retinopathy. Their research team has developed an innovative and efficient process of pre-screening in the IR model to identify treatments to be further tested in diabetic animals. IR serves as a useful tool to acutely model retinal neurodegeneration, as well as the vascular endothelial growth factor- (VEGF) dependent retinal vascular permeability. Having identified several promising drugs, they are now focusing on the mechanisms by which limited classes of drugs provide neuroprotection and/or alleviate the vascular permeability response to IR.
With an R01 grant from the NEI, Dr. Thomas Gardner and Dr. Abcouwer are examining the mechanisms by which retinal neurons degenerate during diabetic retinopathy. This work focuses on the interaction of inflammatory and neurotrophic influences in the diabetic retina. It is based on the observations that cytokines and hyperglycemic conditions become toxic to retinal neurons only in the absence of neurotrophic stimulation. Thus, the objective is to understand the crosstalk between apoptotic signaling pathways caused by hyperglycemia and inflammation with protective neurotrophic signaling pathways. Dr. Abcouwer is examining the interaction between the glucose-responsive thioredoxin-interacting protein (Txnip) and its downstream effecter, apoptosis-signal-regulating kinase (ASK) with the anti-apoptotic PI3K/AKT pathway. The work will further our understanding of how these pathways interact to influence mitochondrial function, reactive-oxygen species generation, the mitochondrial apoptotic pathway, as well as pro- and anti-apoptotic gene expression.
Phase-contrast micrograph of culture mouse microglial cell showing complex ramification of processes used to sense the local tissue environment.
Dr. Abcouwer’s lab is also examining the function and reactions of retinal microglia. These cells represent the innate immune system of all neuronal tissues. They act to monitor the health and function of neurons, detect infection and tissue damage, and maintain homeostasis of neuronal tissue. These cells were once viewed as culprits in neurodegenerative diseases, based on their ability to become fully activated and to produce numerous inflammatory cytokines and destructive reactive oxygen species, thus causing neuronal death and vascular dysfunction. However, it now appears that microglia adopt alternative and anti-inflammatory states of activation that may serve to phagocytose and eliminate damaged tissue as well as limiting and preventing systemic inflammatory reactions to neuronal damage. Very little is known of the states of microglial activation during retinal pathologies; most current studies are limited to describing the migration and morphology of these cells during pathological states. Dr. Abcouwer’s goal is to characterize the various activation states adopted by retinal microglia in diabetic retinopathy and other, more acute retinal pathologies. To this end, his team is developing methods of retinal microglia isolation and flow cytometric analysis to study these cells in detail, as well as methods to manipulate the number and function of these cells in the retina. Their aim is to test the hypothesis that these cells adopt an alternative activation state and thus serve a beneficial role during early diabetic retinopathy, subsequently adopting an inflammatory activated state and playing a detrimental role as the disease progresses and decompensation sets in. Additional studies have perfected methods for maintaining retinal microglia in primary culture and have developed a unique microglial cell line exhibiting temperature-dependent growth and differentiation. These methods will be used to study the interactions of microglia with retinal neurons and vascular cells, the alternative states of microglial activation, and means to prevent these cells from adopting destructive inflammatory activation states.
