Different organs within our bodies have different energy requirements. Such requirements are influenced by the particular function performed by the organ, and the body?s nutritional status. Moreover, energy use of one organ is many times matched by a decrease in energy consumption of another. The liver, for example, will decrease, and sometimes spend energy to support muscle function. However, the central nervous system (CNS) needs to utilize adequate amounts of energy, irrespective of the body?s nutritional status or the metabolic needs of other organs. How the CNS is able to obtain this ?metabolic privilege? is unclear, yet deficits in energy supply to the CNS often underlie diseases such as age-related macular degeneration (AMD) and Alzheimer?s disease. Insulin is the major anabolic hormone in the body. Primarily produced in the pancreas, insulin is released into the blood upon the consumption of food. When sensed by cells in other parts of the body, insulin triggers a cascade of signaling events that allow tissues to take up glucose from circulation. In the context of the retina, insulin is important in homeostasis. Absence of insulin can lead to eye specific diseases such as diabetic retinopathy. Yet how insulin regulates glucose metabolism in the retina is unclear. Crucial to glucose and overall retinal metabolism is the retinal pigment epithelium (RPE). The RPE is a monolayer of pigmented cells forming the blood retinal barrier and recent research has shown that the RPE regulates glucose transport from the periphery into the retina. Preliminary studies in our lab have uncovered that the RPE mediates insulin signaling in the retina. The purpose of this proposal therefore is to test the importance of RPE mediated insulin signaling on glucose metabolism within the retina. We hypothesize that insulin, through the RPE, allows the eyes to maintain an adequate supply of energy at all times, irrespective of nutritional status. Furthermore, we hypothesize that failure in insulin signaling coming from this source can lead to problems in visual function, including neovascularization and photoreceptor atrophy. To test this we will first measure what triggers RPE mediated insulin signaling. We will then measure the impact that knocking out insulin has on glucose uptake by the retina. Finally, we will analyze the downstream consequences that impaired RPE mediated insulin signaling has on retina homeostasis and disease. The results of these studies could provide exciting new concepts on the biology of the eye itself, energy utilization in the retina, and help develop new therapeutics to treat blindness.

Public Health Relevance

The eye is the most metabolically demanding organ in the body. Failure to meet this demand contributes to the development of many retinal degenerative diseases, including age-related macular degeneration, diabetic retinopathy, and retinitis pigmentosa. The aim of this proposal is to understand the mechanisms by which the eye may ensure that glucose is taken from the periphery, into the retina. Research into the mechanisms by which the retina ensures an adequate supply of energy will help further our understanding of eye biology and to the development of new therapeutics for certain eye diseases.

National Institute of Health (NIH)
National Eye Institute (NEI)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1)
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Agarwal, Neeraj
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University of Virginia
Schools of Medicine
United States
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