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.