Loss of vascular homeostasis is a major contributor to the morbidity and mortality of diabetes, and treatments that restore or prevent loss of vascular homeostasis would be of immense value to diabetic patients. However, the processes leading to loss of vascular homeostasis are poorly understood, and effective treatments are not available. The long term goal is to better understand mechanisms underlying the loss of vascular homeostasis in diabetes in order to develop preventive and therapeutic protocols. Dysregulation of the 268 proteasome has been implicated in the loss of vascular homeostasis in diabetes. It appears to involve enhanced 268 proteasome functionality resulting in down regulation of nitric oxide (NO). The preliminary data suggests that NO itself regulates 268 proteasomes, a mechanism that might be compromised in diabetes. Therefore, the objective in this application is to identify how NO regulates 268 proteasomes. The central hypothesis is that eNOS-derived homeostatic levels of nitric oxide, via maintaining the 0-GlcNAc modification of the regulatory complex PA700 (Rpt2), functions as an endogenous inhibitor of 268 proteasomes to preserve vascular homeostasis, which is lost in diabetes. The rationale for the proposed research is that the identified mechanism may help to understand how vascular homeostasis is lost in patients of diabetes, epidemic of which is believed to hit half of this country by 2020. Guided by strong preliminary data, the hypothesis will be tested by pursuing two specific aims: 1) Determine if endothelial NO inhibits 268 proteasome functionality via maintaining 0-GlcNAc modification of the regulatory complex PA700 (Rpt2);and 2): Determine if pharmacologic or genetic strategies that restore eNOS-derived NO or enhance PA700 (Rpt2) 0-GlcNAc modification suppress 268 proteasome functionality and mitigate endothelial dysfunction in diabetes. The approach is innovative, because it utilizes a proteasome reporter system to study diabetic vascular endothelial function. The proposed research is also significant, because it is expected to provide insight into therapeutic interventions in addition to fundamentally advancing the fields of vascular medicine.

Public Health Relevance

The proposed research is relevant to public health, because the discovery of NO-mediated 268 proteasome regulation in the prevention of endothelial dysfunction.is expected to improve understanding of the pathogenesis of vascular homeostasis loss in diabetes. It also bears the hope of developing better preventive and therapeutic protocols to this common abnormality in people with diabetes.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Exploratory Grants (P20)
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University of Oklahoma Health Sciences Center
Oklahoma City
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Wang, Bing; Li, Pui-Kai; Ma, Jian-Xing et al. (2018) Therapeutic Effects of a Novel Phenylphthalimide Analog for Corneal Neovascularization and Retinal Vascular Leakage. Invest Ophthalmol Vis Sci 59:3630-3642
Shin, Younghwa; Moiseyev, Gennadiy; Petrukhin, Konstantin et al. (2018) A novel RPE65 inhibitor CU239 suppresses visual cycle and prevents retinal degeneration. Biochim Biophys Acta Mol Basis Dis 1864:2420-2429
Fu, Shuhua; Dong, Shuqian; Zhu, Meili et al. (2018) VEGF as a Trophic Factor for Müller Glia in Hypoxic Retinal Diseases. Adv Exp Med Biol 1074:473-478
Orock, Albert; Logan, Sreemathi; Deak, Ferenc (2018) Munc18-1 haploinsufficiency impairs learning and memory by reduced synaptic vesicular release in a model of Ohtahara syndrome. Mol Cell Neurosci 88:33-42
Vadvalkar, Shraddha S; Matsuzaki, Satoshi; Eyster, Craig A et al. (2017) Decreased Mitochondrial Pyruvate Transport Activity in the Diabetic Heart: ROLE OF MITOCHONDRIAL PYRUVATE CARRIER 2 (MPC2) ACETYLATION. J Biol Chem 292:4423-4433
He, Xuemin; Cheng, Rui; Park, Kyoungmin et al. (2017) Pigment epithelium-derived factor, a noninhibitory serine protease inhibitor, is renoprotective by inhibiting the Wnt pathway. Kidney Int 91:642-657
Deng, Guotao; Moran, Elizabeth P; Cheng, Rui et al. (2017) Therapeutic Effects of a Novel Agonist of Peroxisome Proliferator-Activated Receptor Alpha for the Treatment of Diabetic Retinopathy. Invest Ophthalmol Vis Sci 58:5030-5042
Du, Mei; Phelps, Eric; Balangue, Michael J et al. (2017) Transgenic Mice Over-Expressing RBP4 Have RBP4-Dependent and Light-Independent Retinal Degeneration. Invest Ophthalmol Vis Sci 58:4375–4383
Jung, Dongju; Xu, Yuechi; Sun, Zhongjie (2017) Induction of anti-aging gene klotho with a small chemical compound that demethylates CpG islands. Oncotarget 8:46745-46755
Shin, Younghwa; Moiseyev, Gennadiy; Chakraborty, Dibyendu et al. (2017) A Dominant Mutation in Rpe65, D477G, Delays Dark Adaptation and Disturbs the Visual Cycle in the Mutant Knock-In Mice. Am J Pathol 187:517-527

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