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 of 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.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY020582-04
Application #
8264355
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
2012-05-01
Budget End
2013-04-30
Support Year
4
Fiscal Year
2012
Total Cost
$448,980
Indirect Cost
$160,247
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
Stem, Maxwell S; Hussain, Munira; Lentz, Stephen I et al. (2014) Differential reduction in corneal nerve fiber length in patients with type 1 or type 2 diabetes mellitus. J Diabetes Complications 28:658-61
Fort, Patrice E; Losiewicz, Mandy K; Pennathur, Subramaniam et al. (2014) mTORC1-independent reduction of retinal protein synthesis in type 1 diabetes. Diabetes 63:3077-90
Abcouwer, Steven F; Gardner, Thomas W (2014) Diabetic retinopathy: loss of neuroretinal adaptation to the diabetic metabolic environment. Ann N Y Acad Sci 1311:174-90
Stem, Maxwell S; Gardner, Thomas W (2013) Neurodegeneration in the pathogenesis of diabetic retinopathy: molecular mechanisms and therapeutic implications. Curr Med Chem 20:3241-50
Abcouwer, Steven F (2013) Angiogenic Factors and Cytokines in Diabetic Retinopathy. J Clin Cell Immunol Suppl 1:
Harris Nwanyanwu, Kristen; Talwar, Nidhi; Gardner, Thomas W et al. (2013) Predicting development of proliferative diabetic retinopathy. Diabetes Care 36:1562-8
Abcouwer, Steven F (2013) Direct effects of PPAR* agonists on retinal inflammation and angiogenesis may explain how fenofibrate lowers risk of severe proliferative diabetic retinopathy. Diabetes 62:36-8
Kaiser, James M; Imai, Hisanori; Haakenson, Jeremy K et al. (2013) Nanoliposomal minocycline for ocular drug delivery. Nanomedicine 9:130-40
Abcouwer, Steven F; Lin, Cheng-Mao; Shanmugam, Sumathi et al. (2013) Minocycline prevents retinal inflammation and vascular permeability following ischemia-reperfusion injury. J Neuroinflammation 10:149
Barber, Alistair J; Gardner, Thomas W; Abcouwer, Steven F (2011) The significance of vascular and neural apoptosis to the pathology of diabetic retinopathy. Invest Ophthalmol Vis Sci 52:1156-63

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