Diabetic retinopathy (DR) is traditionally regarded as a microvascular complication in diabetic retinas. However, it is increasingly recognized that the loss of retinal neuronal function and viability occurs before the onset of retinal microvascular abnormalities in diabetic humans and animals. Diabetes induces photoreceptor degeneration. Cone degeneration is particularly devastating, as cone photoreceptors are responsible for bright and color vision. At present, the mechanisms governing diabetes-induced photoreceptor degeneration are largely unexplored. Recent studies suggest that vascular endothelial growth factor (VEGF), a major angiogenic factor that is up-regulated under hypoxic and diabetic conditions, may play a role as a survival factor for retinal neurons, including photoreceptors. However, VEGF is a therapeutic target of diabetes-induced retinal vascular complications and anti-VEGF agents have been used to develop therapeutics for DR. As VEGF receptor-2 (VEGFR2) and neuropilin-1 (NRP1) are the most abundantly expressed VEGF receptor-like proteins in neuronal cells, identifying the roles and mechanisms of VEGF signaling through VEGFR2 and NRP1 in retinal neurons is paramount to the safety of long-term anti-VEGF treatments for DR. To test our central hypothesis that VEGF signaling through VEGFR2 and NRP1 plays an essential role in preserving photoreceptor function and viability in DR, we will use both in vitro and in vivo models to determine the function and mechanisms of VEGFR2 and NRP1 signaling in photoreceptors.
In Aim 1 we will examine VEGFA/EGFR2 signaling activated pathways, regulation of VEGFR2 activity, and the involvement of NRP1 in VEGF signaling cascade.
In Aim 2 we will determine if the loss of VEGFR2 exacerbates ischemia- or diabetes-induced photoreceptor dysfunction by examining cone density, retinal morphology, and photoreceptor function in rod- or cone-specific VEGFR2 knockout mice.
In Aim 3 we will generate rod- or cone-specific NRP1 knockout mice and characterize photoreceptor function, morphology, and density in these conditional NRP1 knockout mice under ischemic or diabetic conditions.
Our study is relevant to a major public health issue: the function and survival of retinal neurons in ischemia and diabetes. As anti-VEGF agents have been used as a major strategy to develop therapeutics for DR, this preclinical study is likely to reveal important information about the safety of long-term anti-VEGF treatments.
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