Retinopathy, one of the most debilitating complications of diabetes, is the leading cause of acquired blindness among young adults. The clinical studies have shown that retinopathy resists arrest after good control is initiated, and the carry-over effect of prior glycemic exposure on the later course of microvascular complications is commonly termed as 'metabolic memory'. The proposed studies are focused to understand the mechanism responsible for this tendency of incipient retinopathy to halt. The overall hypothesis predicts that 'the resistance of retinopathy to arrest is, in part, due to the continued mitochondrial dysfunction and accumulation of oxidatively modified proteins and DNA in the retinal microvasculature, resulting in irreversible loss of retinal capillary cells'. In support, we have shown that oxidative stress and nitrosylation of retinal proteins continue after re-institution of good glycemic control in rats, the retina experiences mitochondrial dysfunction in diabetes, and overexpression of MnSOD protects the retina from DNA damage.
Aim 1 will determine the role of mitochondrial dysfunction in the retina after good glycemic control is instituted. Using the rat model of metabolic memory we will test the hypothesis that 'superoxide continues to accumulate resulting in mitochondrial dysfunction and formation of oxidatively modified DNA in the vasculature that is difficult to reverse after good control is instituted'.
Aim 2 will investigate the mechanism by which superoxide contributes to the metabolic memory, and will test the hypothesis that 'due to increased superoxide the activity of GAPDH is inhibited resulting in accumulation of AGEs;and increased AGEs result in irreversible changes in retinal microvasculature'.
Aim 3 will determine the effect of inhibiting superoxide accumulation on continued progression of retinopathy after hyperglycemia is reversed. The hypothesis that 'inhibition of superoxide will be capable of directly inhibiting oxidative stress, GAPDH and the biochemical abnormalities influenced by these processes, and thus will inhibit the progression of retinopathy'will be tested in rats by therapeutically inhibiting superoxide accumulation, and in mice overexpressing MnSOD. Characterization of the abnormalities responsible for the resistance of diabetic retinopathy to halt is expected to reveal novel targets for therapies to prevent its progression, and offer patients an opportunity to supplement their best possible glycemic control with adjunct therapies.

National Institute of Health (NIH)
National Eye Institute (NEI)
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Biology and Diseases of the Posterior Eye Study Section (BDPE)
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Neuhold, Lisa
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Wayne State University
Schools of Medicine
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Kowluru, Renu A; Mishra, Manish (2018) Therapeutic targets for altering mitochondrial dysfunction associated with diabetic retinopathy. Expert Opin Ther Targets 22:233-245
Mishra, Manish; Duraisamy, Arul J; Kowluru, Renu A (2018) Sirt1: A Guardian of the Development of Diabetic Retinopathy. Diabetes 67:745-754
Duraisamy, Arul J; Mishra, Manish; Kowluru, Renu A (2017) Crosstalk Between Histone and DNA Methylation in Regulation of Retinal Matrix Metalloproteinase-9 in Diabetes. Invest Ophthalmol Vis Sci 58:6440-6448
Devi, Takhellambam Swornalata; Somayajulu, Mallika; Kowluru, Renu Anjan et al. (2017) TXNIP regulates mitophagy in retinal Müller cells under high-glucose conditions: implications for diabetic retinopathy. Cell Death Dis 8:e2777
Mishra, Manish; Kowluru, Renu A (2017) Role of PARP-1 as a novel transcriptional regulator of MMP-9 in diabetic retinopathy. Biochim Biophys Acta Mol Basis Dis 1863:1761-1769
Kowluru, Renu A; Shan, Yang (2017) Role of oxidative stress in epigenetic modification of MMP-9 promoter in the development of diabetic retinopathy. Graefes Arch Clin Exp Ophthalmol 255:955-962
Kowluru, Renu A; Mishra, Manish (2017) Epigenetic regulation of redox signaling in diabetic retinopathy: Role of Nrf2. Free Radic Biol Med 103:155-164
Mishra, Manish; Lillvis, John; Seyoum, Berhane et al. (2016) Peripheral Blood Mitochondrial DNA Damage as a Potential Noninvasive Biomarker of Diabetic Retinopathy. Invest Ophthalmol Vis Sci 57:4035-44
Kowluru, Renu A; Shan, Yang; Mishra, Manish (2016) Dynamic DNA methylation of matrix metalloproteinase-9 in the development of diabetic retinopathy. Lab Invest 96:1040-9
Mishra, Manish; Flaga, Jadwiga; Kowluru, Renu A (2016) Molecular Mechanism of Transcriptional Regulation of Matrix Metalloproteinase-9 in Diabetic Retinopathy. J Cell Physiol 231:1709-18

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