The overall goal of this proposal is to understand how diabetes impairs the survival of retinalneurons. The specific objective is to investigate how diabetes-induced hyperglycemia and inflammatorymediators 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 ofretinal neurons will lead to improved means to prevent vision loss in diabetes and other retinaldegenerations. Diabetes damages the retina by multiple insults, including hyperglycemia, inflammation and alteredpro-survival signaling, but the mechanisms that cause neurons to die remain uncertain. Growth factorsignaling through Akt (protein kinase B) is central to the survival of neurons, and is impaired as a sharedfeature 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 acomponent of early diabetic retinopathy. The investigators have demonstrated that retinal pro-survivalsignaling via the insulin receptor and Akt is normally activated by insulin, insulin-like growth factors andlight, and diabetes reduces this basal pro-survival activity concomitant with the onset of retinal neuronsdeath. We have shown that hyperglycemia disrupts the survival of retinal neurons in culture and now findthat cytokines block the neurotrophic actions of growth factors. Reduction of hyperglycemia with phlorizintreatment 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 celldeath. We have also generated a novel mouse model with conditional retinal insulin receptor knockdownthat provides a powerful tool to examine the role of retinal pro-survival signaling. Together, these datademonstrate that insulin receptor/Akt signaling is a key survival pathway for retinal neurons. Thus, wepropose the general hypothesis that hyperglycemia and inflammation impair neurotrophin-mediatedsurvival of retinal neurons in diabetes.
Three specific aims using biochemical, molecular and geneticapproaches in retinal neuron cultures, diabetic rats, and mice with knockdown of the insulin receptor/Aktpathway will test the hypothesis. A strong interdisciplinary research team of will elucidate the mechanismsby which hyperglycemia and cytokines impair neurotrophin-mediated survival of retinal neurons in a culturesystem and in diabetic rats. We will also determine the impact of insulin receptor/Akt signaling on retinalneuron 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.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY020582-03
Application #
8197200
Study Section
Biology and Diseases of the Posterior Eye Study Section (BDPE)
Program Officer
Shen, Grace L
Project Start
2010-05-01
Project End
2014-04-30
Budget Start
2011-05-01
Budget End
2012-04-30
Support Year
3
Fiscal Year
2011
Total Cost
$445,687
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Shah, Anjali R; Gardner, Thomas W (2017) Diabetic retinopathy: research to clinical practice. Clin Diabetes Endocrinol 3:9
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
Abcouwer, Steven F (2017) Müller Cell-Microglia Cross Talk Drives Neuroinflammation in Diabetic Retinopathy. Diabetes 66:261-263
Ghodasra, Devon H; Fante, Ryan; Gardner, Thomas W et al. (2016) Safety and Feasibility of Quantitative Multiplexed Cytokine Analysis From Office-Based Vitreous Aspiration. Invest Ophthalmol Vis Sci 57:3017-23
Gardner, Thomas W; Chew, Emily Y (2016) Future opportunities in diabetic retinopathy research. Curr Opin Endocrinol Diabetes Obes 23:91-6
Cohen, Steven R; Gardner, Thomas W (2016) Diabetic Retinopathy and Diabetic Macular Edema. Dev Ophthalmol 55:137-46
Beli, Eleni; Dominguez 2nd, James M; Hu, Ping et al. (2016) CX3CR1 deficiency accelerates the development of retinopathy in a rodent model of type 1 diabetes. J Mol Med (Berl) 94:1255-1265
Stem, M S; Dunbar, G E; Jackson, G R et al. (2016) Glucose variability and inner retinal sensory neuropathy in persons with type 1 diabetes mellitus. Eye (Lond) 30:825-32
Bavinger, J Clay; Dunbar, Grace E; Stem, Maxwell S et al. (2016) The Effects of Diabetic Retinopathy and Pan-Retinal Photocoagulation on Photoreceptor Cell Function as Assessed by Dark Adaptometry. Invest Ophthalmol Vis Sci 57:208-17

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