The objective of the PI's research is to define the contribution of amino-carbonyl reactions which occur between reducing sugars and protein amino groups (so-called Maillard reaction) in the aging of the human leans. In vitro, this reaction leads to the formation of protein fluorophores, chromophores, crosslinks and photosensitizers. Considerable progress, including from our own laboratory, As been achieved in recent years will now implicates and Maillard reaction in molecular changes in normal aging of lens crystallins, and at an accelerated rate in diabetes. In short, incubation of lens crystallins with reducing sugar or ascorbic acid was found to delicate most if not all the changes observed in the aging and cataractous human lens.
Three specific aims are proposed.
Specific aim I will be to elucidate the mechanism of formation of pentodilysine, and advanced Maillard reaction product discovered in our laboratory which has the unique ability to respond to moderate hyperglycemic stress induced by diabetes in the leans, in contrast to pentosidine, a glycoxidation product which in the lens responds only to high glycemic stress.
Specific aim II will be to establish a metabolic map of ascorbate catabolites in the lens using a novel, unequivocal methodology based on fluorine labeled ascorbate and noninvasive magnetic resonance imaging in combination with NMR and GC/MS. These experiments will be carried out in collaboration with an expert in fluorine chemistry and an expert in solid state spectroscopy and MRI imaging. They are expected to provide an insight into the question of how ascorbate oxidation products are detoxified in vivo, and help test the hypothesis that impairment in ascorbate processing forms the basis for accelerated lenticular aging and cataractogenesis in some individuals. Finally, in specific aim III, the PI will initiate research into the endogenous and pharmacological mechanisms of ascorbate detoxification. In particular, he will test the novel hypothesis that the highly reactive ascorbate catabolites can be chemically deactivated by H202 and glutathione, or trapped by the guanidino groups of N-acetyl arginine and aminoguanidine both of which have been found to have anticataract properties. The reaction products of these agents will be characterized and utilized as markers in anticataract therapy.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY007099-12
Application #
2710989
Study Section
Visual Sciences A Study Section (VISA)
Project Start
1987-08-01
Project End
2002-07-31
Budget Start
1998-08-01
Budget End
1999-07-31
Support Year
12
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Case Western Reserve University
Department
Pathology
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Whitson, Jeremy A; Wilmarth, Phillip A; Klimek, John et al. (2017) Proteomic analysis of the glutathione-deficient LEGSKO mouse lens reveals activation of EMT signaling, loss of lens specific markers, and changes in stress response proteins. Free Radic Biol Med 113:84-96
Fan, Xingjun; Monnier, Vincent M; Whitson, Jeremy (2017) Lens glutathione homeostasis: Discrepancies and gaps in knowledge standing in the way of novel therapeutic approaches. Exp Eye Res 156:103-111
Feng, Weiyi; Rosca, Mariana; Fan, Yuxuan et al. (2017) Gclc deficiency in mouse CNS causes mitochondrial damage and neurodegeneration. Hum Mol Genet 26:1376-1390
Whitson, Jeremy A; Sell, David R; Goodman, Michael C et al. (2016) Evidence of Dual Mechanisms of Glutathione Uptake in the Rodent Lens: A Novel Role for Vitreous Humor in Lens Glutathione Homeostasis. Invest Ophthalmol Vis Sci 57:3914-25
Sell, David R; Sun, Wanjie; Gao, Xiaoyu et al. (2016) Skin collagen fluorophore LW-1 versus skin fluorescence as markers for the long-term progression of subclinical macrovascular disease in type 1 diabetes. Cardiovasc Diabetol 15:30
Fan, Xingjun; Zhou, Sheng; Wang, Benlian et al. (2015) Evidence of Highly Conserved ?-Crystallin Disulfidome that Can be Mimicked by In Vitro Oxidation in Age-related Human Cataract and Glutathione Depleted Mouse Lens. Mol Cell Proteomics 14:3211-23
Fessel, Gion; Li, Yufei; Diederich, Vincent et al. (2014) Advanced glycation end-products reduce collagen molecular sliding to affect collagen fibril damage mechanisms but not stiffness. PLoS One 9:e110948
Monnier, Vincent M; Sun, Wanjie; Sell, David R et al. (2014) Glucosepane: a poorly understood advanced glycation end product of growing importance for diabetes and its complications. Clin Chem Lab Med 52:21-32
Linetsky, Mikhail; Raghavan, Cibin T; Johar, Kaid et al. (2014) UVA light-excited kynurenines oxidize ascorbate and modify lens proteins through the formation of advanced glycation end products: implications for human lens aging and cataract formation. J Biol Chem 289:17111-23
Monnier, Vincent M; Sell, David R; Strauch, Christopher et al. (2013) The association between skin collagen glucosepane and past progression of microvascular and neuropathic complications in type 1 diabetes. J Diabetes Complications 27:141-9

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