Vascular endothelial growth factor (VEGF) is a major pathogenic factor for wet age-related macular degeneration (AMD) and diabetic retinopathy (DR), leading causes of blindness in the US. Intensive studies on wet AMD and DR have led to the development of anti-VEGF strategy for treating blood-retina barrier (BRB) breakdown in these diseases. To investigate the functional significance of VEGF signaling in major retinal supporting cells, Mller glia, we disrupted VEGF receptor-2 (VEGFR2) in mice and observed a significant loss of Mller cells, accelerated retinal neuron degeneration, and a substantial reduction of two neurotrophins: brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) in the retina in diabetes/hypoxia. In this study, we will determine the mechanism of VEGF signaling-mediated Mller cell viability, evaluate the significance of VEGF signaling in the production of neurotrophins, and explore therapeutic potential of supplying neurotrophins for neuroprotection in diabetic or hypoxic animals. Our study will contribute to the basis for establishing a general strategy to treat neuronal pathology in DR and other hypoxic retinal diseases and provide mechanistic insights for Mller glia as a cellular source of neuro-protectants in these diseases.
Our study is relevant to a major public health issue: neuroprotection for retinal neurons in diabetes and other hypoxic retinal diseases. The experiments proposed in this application will allow us to perform preclinical investigation for the treatment and preservation of vision in patients with diabetic retinopathy, age-related macular degeneration, and other hypoxic retinal diseases
| Fu, Shuhua; Dong, Shuqian; Zhu, Meili et al. (2018) VEGF as a Trophic Factor for Müller Glia in Hypoxic Retinal Diseases. Adv Exp Med Biol 1074:473-478 |
| Le, Yun-Zheng (2017) VEGF production and signaling in Müller glia are critical to modulating vascular function and neuronal integrity in diabetic retinopathy and hypoxic retinal vascular diseases. Vision Res 139:108-114 |
| Hu, Jianyan; Li, Tingting; Du, Xinhua et al. (2017) G protein-coupled receptor 91 signaling in diabetic retinopathy and hypoxic retinal diseases. Vision Res 139:59-64 |
