Role of Notch Signaling in Diabetic Retinopathy
Diabetic retinopathy is the most common eye disease affecting both type 1 and type 2diabetics, and is a leading cause of blindness in adults in the U.S. One of the first clinical signs of diabetic retinopathy is pericyte dropout, which leads to leaky blood vessels, microaneurysms and disease progression. The cause of pericyte dropout is unknown, thus treatments to prevent or halt this early disease process are unavailable. Accordingly, understanding the mechanisms of pericyte dropout is the first step towards providing new avenues for treatment of diabetic retinopathy.A long-term goal of our lab is to define the actions of Notch receptor signaling in normal and diseased blood vessels. To this end, werecently characterized the loss-of-function phenotype of the pericyte-expressed Notch3 gene in the mouse retinal vasculature. Notch3 null mice, while viable, display a progressive loss of retinal pericytes, mimicking pericyte dropout.Notch3 is the causative gene for the vascular neuropathy disease CADASIL in humans, which is associated with smooth muscle/pericyte degeneration.These published data support acausative role for Notch signaling in pericyte dropout in diabetic retinopathy, however no direct link has been established between Notch activity and the disease. Therefore, the overall goal of this application is to define Notch signaling in relation to pericyte dropout and diabetic retinopathy. Wehypothesizethat perturbed Notch signaling has a central role in pericyte dropout leading to progressive stages of diabetic retinopathy. We will objectively test our hypothesis by defining Notch activity in a mouse model of diabetic retinopathy and by determining the requirement of Notch signaling in disease progression. Data generated in our lab indicate that Notch signaling functions in pericyte dropout via a mechanism that involves signaling between vascular endothelial cells andpericytes. Our lab first defined a function for Notch3 in retinal pericyte homeostasis, and we and others provided the first evidence of the importance of the membrane-bound Notch ligand, Jagged1 signaling from endothelial cells to pericytes/smooth muscle cells. Additional preliminary data havedemonstrated that Notch signaling is blunted in high glucose conditions. We will build upon our current findings of Notch signaling in pericyte function to define the pathwaysinvolved in diabetic disease conditions with three specific aims:Aim 1)Determine the activity of Notch signaling in a mouse model of diabetic retinopathy. Aim 2) Define the role of Notch signaling on endothelial cell and pericyte crosstalk under high glucose-induced diabetic conditions. Aim 3)Characterize the effect of genetic ablation of Notch signaling on pericyte dropout and progression of diabetic retinopathy. The expected outcomes from the completion of these aims will be a significantadvancement in our understanding of pericyte dropout. These experiments will provide novel mechanistic insight to the causes of pericyte loss in diabetic conditions, and offernew avenues for therapeutic intervention and the control of diabetic retinopathy.
Contact Information
Brenda J. Lilly, Ph.D.
Associate Professor
WB4233
Center for Cardiovascular and Pulmonary Research
Nationwide Children’s Research Institute
Department of Pediatrics, The Ohio State University
700 Children’s Drive
Columbus, OH 43205
Phone: 614-355-5750 (Office)
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