People with diabetes are 25 times more likely to become blind than non-diabetics developing diabetic retinopathy (DR). Two major cellular events, neurodegeneration and retinal vasculature dysfunction, are known pathophysiological biomarkers of DR. Currently, research on retinal dysfunction, including reduced cone sensitivity, delayed activation of the cone phototransduction cascade, selective loss of S cones, glial abnormalities, and the thinning of both the nerve fiber layer and the retinal ganglion cell layer, in patients with DR has been delayed due to the lack or inaccessibility of an appropriate animal model. Several animal models of DR have been used to study the cellular and molecular basis of DR pathogenesis. While these models have recently demonstrated that hyperglycemia is sufficient to injure neurons, it is not yet clearly understood how cone photoreceptor cells deteriorate with compromised insulin tolerance. The latter is particularly important, given that these animal models have rod-dominant retinas. In contrast, northern tree shrews (Tupaia belangeri ) are one of the closest living relatives to primates, and they have a cone-dominant retina with a ?fovea-like? cone density in the central region. Therefore, we hypothesize that tree shrews are an ideal and unique model of DR that accurately emulate critical aspects of human DR and will further translational research aimed at restoring vision in diabetic patients. This model would also bridge research conducted with NHP and rodents, allowing for critical data interpretation of potential DR biomarkers. First, we will verify whether hyperglycemia is associated with cone photoreceptor dysfunction and cell loss. Second, we will validate whether the retina of diabetic tree shrews experiences a metabolic equilibrium disturbance during retinopathy progression like other human diabetic tissues. Finally, we will investigate whether compromised permeability, pericyte loss, and formation of acellular capillaries lead to vascular histopathology in diabetic tree shrews. By generating and delineating a new non-primate model of DR with the most striking and most novel phenotypes, such as cone photoreceptor dysfunction, retinal metabolic failure, and vascular abnormalities, we can lay the groundwork for a better molecular understanding of DR pathophysiology and open an avenue for improving the treatment of human eye diseases.
We propose to develop and validate a tree shrew model of diabetic retinopathy that accurately mimics neuro- vascular retinal pathogenesis seen in patients with diabetes. By generating and delineating a new model with the most novel phenotypes such as cone photoreceptor dysfunction, we lay the groundwork for a better understanding of DR pathophysiology and open an avenue for improving the treatment of human eye diseases. .
