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Abcouwer, Steven, PhD

University of Michigan, Ann Arbor, Michigan

Project Title:

Role of Interferon-Gamma in the Retinal Neuroinflammatory Response to Diabetes

Grant Number:

7-13-IN-01

Type of Grant:

Innovation

General Research Subject:

Both Type 1 and Type 2 Diabetes

Project Start Date:

Jul 1, 2013

Project End Date:

Jun 30, 2015

Focus:

Complications, Complications\Ocular, Signal Transduction (Non-Insulin Action), Signal Transduction (Non-Insulin Action)\Cytokines and Apoptosis, Signal Transduction (Non-Insulin Action)\Transgenic Models

Research Description



It is well established that inflammation plays a causal role in diabetic complications, including diabetic retinopathy (DR). The diabetic retina exhibits a particular type of low-grade neural inflammation that contributes to the risk of developing sight-threatening DR. However, we do not know how diabetes causes the inflammatory changes in the retina. We hypothesize that a cytokine called interferon-gamma is necessary for many of the inflammatory alterations observed in diabetic retinopathy. This hypothesis is based on several observations that are fully constant with the effects of interferon-gamma on neural tissues. For example, some protein found to be increased in the aqueous and vitreous of patients with DR are known as interferon-responsive factors. Many gene expression changes observed in diabetic rodent retinas include interferon-responsive genes. Levels of interferon-gamma protein are increased in the vitreous of diabetic mice. In addition, in diabetic retinas immune cells known as microglia exhibit increased expression of a protein on their surface that is indicative of interferon-gamma stimulation. We will test the role of interferon-gamma in a murine model by contrasting the progression of retinal inflammatory and vascular changes in normal mice and in mice lacking the interferon-gamma gene and in mice with microglia that cannot respond to interferon-gamma stimulation. Demonstration that interferon-gamma is a key regulator of the inflammation and microglial responses observed during diabetic retinopathy would greatly aid the development of therapeutic approaches to curtail inflammatory immune responses in the diabetic retina and prevent the progression of DR.

Research Profile



What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
Diabetic retinopathy mechanisms. Using mouse models of diabetes, the research investigates the mechanisms by which neuroinflammation occurs in the diabetic retina. I particular, it examine the role of interferon-gamma in the processes of retinal diabetic neuroinflammation.

If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
Although there are treatments for diabetic retinopathy, these treatments are very invasive, cause complications, and are effective for only a fraction of diabetic retinopathy patients. The presently-available treatments are interventions applied only when diabetic retinopathy is severe. There are no preventative treatments for diabetic retinopathy. We know that the progression of diabetic retinopathy includes inflammation in the retina, but we do not know what causes this inflammatory response. This research will provide clues to the origins of inflammation in the diabetic retina with the hope that understanding this process will lead to preventative treatments for diabetic retinopathy.

Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
My overarching goal is to understand the molecular mechanisms that lead to the development and progression of diabetic retinopathy. This innovative award allows my research group to test a compelling theory regarding the origins of inflammation in the diabetic retina. This particular project is in its infancy, and this innovative award will allow the initially testing of the hypotheses.

In what direction do you see the future of diabetes research going?
Although a cure for diabetes is always most desirable, prevention and treatment of diabetic complications will become a greater imperative as the quality of life of increasing numbers of people are seriously threatened and severely impacted by these complications.