The goal of this project is to determine the pathogenesis of and neuroprotection against retinal ganglion cell (RGC) death in diabetic retinopathy. Many RGCs die within the first 2 years of disease onset. The RGC death is thought to be due to overstimulation of the N-methyl-D-aspartate (NMDA) receptor that leads to excessive levels of intracellular calcium, which triggers the cell death cascade. Glutamate, which is elevated in the vitreous body and retina of diabetic patients, is the primary excitotoxin that activates the NMDA receptor. Homocysteine, which accumulates in the plasma of diabetic patients, induces RGC death when injected intravitreally. NMDA receptor activation requires co-activation of its glycine binding site and D-serine is the endogenous physiologic ligand for this site. Serine racemase is the enzyme responsible for the endogenous generation of D-serine. One of the goals of the project is to elucidate the molecular events involved in the extracellular accumulation of the MDA receptor agonists, glutamate and homocysteine, and the co-agonist D-serine. D-serine and serine racemase are expressed in retina, but their involvement in diabetes has not been investigated.
AIM 1 will test the hypothesis that diabetes is associated with increased levels of D-serine and serine racemase leading to enhanced activation of the NMDA receptor by glutamate and homocysteine.
AIM 2 will test the hypothesis that diabetes is associated with altered function of transport systems for glutamate (EAATs, x[c-]), homocysteine and D-serine (ATB0,+) and that their altered function may provide the molecular basis for the diabetes-associated increase in extracellular levels of glutamate, homocysteine and D-serine. Therapeutic intervention strategies targeted at blocking NMDA receptor stimulation could prevent RGC death and may delay other manifestations of diabetic retinopathy. Type 1 sigma receptor (sigmaR1) is a nonopiate, nonphencyclidine binding site that demonstrates robust neuroprotective properties including inhibition of ischemia-induced glutamate release and depressed neuronal responsivity to NMDA receptor stimulation. SigmaR1 is expressed abundantly in RGCs and continues to be expressed under hyperglycemic conditions. Agonists specific for sigmaR1 may have potential as therapeutic agents in providing neuroprotection in the early stages of diabetic retinopathy. Our preliminary data show that (+)-pentazocine, a sigmaR1 agonist, prevents RGC death in vitro induced by glutamate and homocysteine and in vivo induced by diabetes.
AIM 3 will test the hypothesis that sigmaR1 agonists will be protective against RGC death characteristic of diabetic retinopathy.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY014560-02
Application #
6838764
Study Section
Special Emphasis Panel (ZRG1-CDF-1 (02))
Program Officer
Dudley, Peter A
Project Start
2004-01-01
Project End
2007-12-31
Budget Start
2005-01-01
Budget End
2005-12-31
Support Year
2
Fiscal Year
2005
Total Cost
$321,750
Indirect Cost
Name
Georgia Health Sciences University
Department
Biology
Type
Schools of Medicine
DUNS #
966668691
City
Augusta
State
GA
Country
United States
Zip Code
30912
Chaudhary, Kapil; Promsote, Wanwisa; Ananth, Sudha et al. (2018) Iron Overload Accelerates the Progression of Diabetic Retinopathy in Association with Increased Retinal Renin Expression. Sci Rep 8:3025
Smith, Sylvia B; Wang, Jing; Cui, Xuezhi et al. (2018) Sigma 1 receptor: A novel therapeutic target in retinal disease. Prog Retin Eye Res 67:130-149
Mysona, Barbara; Kansara, Neil; Zhao, Jing et al. (2017) The Role of Sigma 1 Receptor as a Neuroprotective Target in Glaucoma. Adv Exp Med Biol 964:299-307
Wang, Jing; Cui, Xuezhi; Roon, Penny et al. (2017) The Role of Sigma1R in Mammalian Retina. Adv Exp Med Biol 964:267-284
Wang, Jing; Saul, Alan; Cui, Xuezhi et al. (2017) Absence of Sigma 1 Receptor Accelerates Photoreceptor Cell Death in a Murine Model of Retinitis Pigmentosa. Invest Ophthalmol Vis Sci 58:4545-4558
Smith, Sylvia B (2017) Introduction to Sigma Receptors: Their Role in Disease and as Therapeutic Targets. Adv Exp Med Biol 964:1-4
Saul, Alan B; Cui, Xuezhi; Markand, Shanu et al. (2017) Detailed electroretinographic findings in rd8 mice. Doc Ophthalmol 134:195-203
Promsote, Wanwisa; Powell, Folami Lamoke; Veean, Satyam et al. (2016) Oral Monomethyl Fumarate Therapy Ameliorates Retinopathy in a Humanized Mouse Model of Sickle Cell Disease. Antioxid Redox Signal 25:921-935
Wang, Jing; Saul, Alan; Roon, Penny et al. (2016) Activation of the molecular chaperone, sigma 1 receptor, preserves cone function in a murine model of inherited retinal degeneration. Proc Natl Acad Sci U S A 113:E3764-72
Wang, Jing; Cui, Xuezhi; Roon, Penny et al. (2016) Role of Sigma 1 Receptor in Retinal Degeneration of the Ins2Akita/+ Murine Model of Diabetic Retinopathy. Invest Ophthalmol Vis Sci 57:2770-81

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