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University of North Carolina at Chapel Hill
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Using new mouse models to identify antioxidant roles in diabetic nephropathy
Diabetic nephropathy (DN) is the single largest cause of end-stage renal disease. Although drug therapy has made progress, renal failure remains. Oxidative stress is implicated in the development of DN. Hence, a variety of antioxidants have been used for DN therapy. However, most clinical trials for antioxidant therapy are disappointed. One possibility is that the role of oxidative stress in the development of DN is dependent on the endogenous antioxidant levels in patients. To test my hypothesis that the endogenous LA level is negatively correlated with development of DN, we have created a group of lipoic acid synthase (Lias) mice with genetically varied levels of Lias gene expression. They have been crossed with diabetic mouse model. In addition, identification of early oxidatitive stress markers for DN should help incorporate the use of these markers and antioxidants into the early diagnosis and therapy. Lipoic acid (LA) is a strong antioxidant and is an essential cofactor in mitochondrial enzyme complexes involving energy generation. LA is produced by lipoic acid synthase (Lias) in mitochondria and has the potential to protect mitochondria. Overproduction of superoxide by the mitochondria during diabetes has been postulated as the primary initiating event in DN. Nitric oxide (NO) also impairs mitochondrial function and contributes to DN development. S-nitrosylation has recently emerged as a major route through which NO bioactivity serves NO-related signals. Currently, S-nitrosylated proteins have not been identified in of DN and its potential regulation by LA has not been studied. I postulate that LA protects mitochondria through regulation of mitochondrial protein S-nitrosylation and quenching superoxide. The aims of my proposal are to apply advanced techniques on this unique animal model; 1) to identify sensitive biomarkers that could be used for early diagnosis and antioxidant therapy in the patients with low antioxidant capacity; 2) to define the role of antioxidant/oxidative stress in DN; 3) to seek a better understanding of the mechanism by which LA protects mitochondria, and 4) to treat LA for a rescue study would strengthen the findings of these studies. This project will provide valuable information for improving the diagnostic and therapeutic outcomes of DN patients.
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Using new mouse models to identify antioxidant roles in diabetic nephropathy (Yi, Xianwen)
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Year: 2016; Items: 1
Influence of Different Levels of Lipoic Acid Synthase Gene Expression on Diabetic Nephropathy.
Xu L, Hiller S, Simington S, Nickeleit V, Maeda N, James LR, Yi X
, 2016 (11)
Year: 2014; Items: 1
a-Lipoic acid protects mitochondrial enzymes and attenuates lipopolysaccharide-induced hypothermia in mice.
Hiller S, DeKroon R, Xu L, Robinette J, Winnik W, Alzate O, Simington S, Maeda N, Yi X
Free radical biology & medicine
, 2014 (71), 362 - 367
Year: 2013; Items: 1
Diabetic atherosclerosis in APOE*4 mice: synergy between lipoprotein metabolism and vascular inflammation.
Johnson LA, Kim HS, Knudson MJ, Nipp CT, Yi X, Maeda N
Journal of lipid research
, 2013 (54), 386 - 396
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The DiaComp Steering Committee is the governing body of the consortium. The principle function of this committee is to guide the scientific direction of the consortium. This is accomplished by creating various subcommittees necessary to advance the scientific goals and providing guidance to the broader complications research community. Policies for the consortium are developed through consultation with the
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The DiaComp Nephropathy Committee has the principal function of furthering the mission of the consortium with regard to diabetic kidney disease.
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Please acknowledge all posters, manuscripts or scientific materials that were generated in part or whole using funds from the Diabetic Complications Consortium(DiaComp) using the following text:
Financial support for this work provided by the NIDDK Diabetic Complications Consortium (RRID:SCR_001415, www.diacomp.org), grants DK076169 and DK115255
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