Modulating retinal lipid biogenesis in diabetes for therapeutic effects

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Project Summary Diabetic retinopathy is an increasingly common cause of visual impairment and blindness among adults. Modern therapy has become increasingly effective, but remains insufficient to prevent vision loss in a sizable proportion of patients. Early-acting and efficacious new remedies are needed, especially since the prevalence of worldwide disease is increasing. A barrier to accomplishing this goal is a poor understanding of the earliest causes of retinal injury in diabetes. In this application, we will address this barrier by studying early changes in retinal metabolism during diabetes – changes that are likely to contribute to disease onset and that can be targeted for therapeutic purposes. Hyperglycemia is the hallmark of all forms of diabetes and is directly related to its complications, including diabetic retinopathy. Since glucose is the primary fuel of the retina, we investigated what pathological effects might occur due to its excess supply in diabetes. Specifically, we discovered that diabetes is associated with a fundamental shift in retinal metabolism away from tissue break down (catabolism) and towards tissue building (anabolism). Among the largest changes is that of lipid biosynthesis, a pathway responsible for generating a ubiquitous medium-chain fatty acid in mammalian cells, palmitate. In diabetes, retinal palmitate synthesis is elevated by 70% compared to non-diabetic controls. Using targeted genetic manipulation of the enzymes in the synthesis pathway, we determined that reduction of palmitate prevents vision loss in diabetes whereas elevating its production accelerates the onset of visual abnormalities. We now ask how such signals are related to disease development and what specific molecules are involved. Towards these goals, we recently found that excess palmitate in the diabetic retina impacts several retinal enzymes that are regulated by S-palmitoylation. The largest change was seen in retinal Ryanodine Receptor 2 (Ryr2) – an intracellular ion channel that regulates calcium homeostasis – as it is hyper-palmitoylated in diabetes compared to non-diabetic controls. In this application we will determine whether this molecular change is associated with pathology and whether it can be reversed for therapeutic effects. We will address three major aims: (1) define the effect of diabetes on retinal Ryr2 palmitoylation and its functional consequences; (2) delineate whether Ryr2-associated calcium flux in rods is dependent on retinal lipid biogenesis; and (3) determine whether improving retinal lipogenic signaling in diabetes reduces diabetic retinopathy severity. By accomplishing these aims, we could uncover essential root causes of diabetic retinopathy and we may introduce novel targets for therapy directed at a very early stage of the disease process.