The overall goal of this proposal is to understand how diabetes impairs the survival of retinal neurons. The specific objective is to investigate how diabetes-induced hyperglycemia and inflammatory mediators accelerate the death of retinal neurons by reducing neurotrophin-mediated signaling pathways. The rationale for this proposal is that understanding the mechanisms that compromise the survival of retinal neurons will lead to improved means to prevent vision loss in diabetes and other retinal degenerations. Diabetes damages the retina by multiple insults, including hyperglycemia, inflammation and altered pro-survival signaling, but the mechanisms that cause neurons to die remain uncertain. Growth factor signaling through Akt (protein kinase B) is central to the survival of neurons, and is impaired as a shared feature of diabetes, systemic infections, immune-mediated inflammation, and degenerative brain diseases. Numerous clinical and animal studies have now established diabetes-induced death of retinal neurons as a component of early diabetic retinopathy. The investigators have demonstrated that retinal pro-survival signaling via the insulin receptor and Akt is normally activated by insulin, insulin-like growth factors and light, and diabetes reduces this basal pro-survival activity concomitant with the onset of retinal neurons death. We have shown that hyperglycemia disrupts the survival of retinal neurons in culture and now find that cytokines block the neurotrophic actions of growth factors. Reduction of hyperglycemia with phlorizin treatment reduces the death of retinal neurons and restores pro-survival signaling in diabetic rats. Moreover, ocular delivery of growth factors also augments pro-survival signaling and reduces retinal cell death. We have also generated a novel mouse model with conditional retinal insulin receptor knockdown that provides a powerful tool to examine the role of retinal pro-survival signaling. Together, these data demonstrate that insulin receptor/Akt signaling is a key survival pathway for retinal neurons. Thus, we propose the general hypothesis that hyperglycemia and inflammation impair neurotrophin-mediated survival of retinal neurons in diabetes.
Three specific aims using biochemical, molecular and genetic approaches in retinal neuron cultures, diabetic rats, and mice with knockdown of the insulin receptor/Akt pathway will test the hypothesis. A strong interdisciplinary research team will elucidate the mechanisms by which hyperglycemia and cytokines impair neurotrophin-mediated survival of retinal neurons in a culture system and in diabetic rats. We will also determine the impact of insulin receptor/Akt signaling on retinal neuron survival and vision in diabetes using novel genetically modified mice.

Public Health Relevance

This proposal is intended to determine why the nerve cells in the retina that are most critical for vision die in diabetes. We will test the hypothesis that excess glucose and inflammatory molecules suppress the normal effects of hormones that keep nerve cells alive. The projected outcome is to have better means to maintain the health of retinal nerve cells in persons with diabetes to preserve vision and reduce the need for laser treatments.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Biology and Diseases of the Posterior Eye Study Section (BDPE)
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Neuhold, Lisa
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Pennsylvania State University
Schools of Medicine
United States
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Kiang, Lee; Ross, Bing X; Yao, Jingyu et al. (2018) Vitreous Cytokine Expression and a Murine Model Suggest a Key Role of Microglia in the Inflammatory Response to Retinal Detachment. Invest Ophthalmol Vis Sci 59:3767-3778
Simó, Rafael; Stitt, Alan W; Gardner, Thomas W (2018) Neurodegeneration in diabetic retinopathy: does it really matter? Diabetologia 61:1902-1912
Rajala, Ammaji; Wang, Yuhong; Abcouwer, Steven F et al. (2018) Developmental and light regulation of tumor suppressor protein PP2A in the retina. Oncotarget 9:1505-1523
Sundstrom, Jeffrey M; Hernández, Cristina; Weber, Sarah R et al. (2018) Proteomic Analysis of Early Diabetic Retinopathy Reveals Mediators of Neurodegenerative Brain Diseases. Invest Ophthalmol Vis Sci 59:2264-2274
Abramoff, Michael D; Fort, Patrice E; Han, Ian C et al. (2018) Approach for a Clinically Useful Comprehensive Classification of Vascular and Neural Aspects of Diabetic Retinal Disease. Invest Ophthalmol Vis Sci 59:519-527
Shah, Anjali R; Gardner, Thomas W (2017) Diabetic retinopathy: research to clinical practice. Clin Diabetes Endocrinol 3:9
Wang, Sophia Y; Andrews, Chris A; Herman, William H et al. (2017) Incidence and Risk Factors for Developing Diabetic Retinopathy among Youths with Type 1 or Type 2 Diabetes throughout the United States. Ophthalmology 124:424-430
Gardner, Thomas W; Sundstrom, Jeffrey M (2017) A proposal for early and personalized treatment of diabetic retinopathy based on clinical pathophysiology and molecular phenotyping. Vision Res 139:153-160
Wang, Sophia Y; Andrews, Chris A; Gardner, Thomas W et al. (2017) Ophthalmic Screening Patterns Among Youths With Diabetes Enrolled in a Large US Managed Care Network. JAMA Ophthalmol 135:432-438
Gardner, Thomas W; Davila, Jose R (2017) The neurovascular unit and the pathophysiologic basis of diabetic retinopathy. Graefes Arch Clin Exp Ophthalmol 255:1-6

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