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Oxidative Stress, microRNA, and Hyper-Contractility in Diabetes
Impairment of gastrointestinal motility, such as delayed or rapid gastric emptying, delayed intestinal transit, and constipation are prevalent in patients with Type I and Type II diabetes and cause considerable morbidity. Numerous studies have used animal models to show that depletion of enteric nNOS neurons and interstitial cells of Cajal contributes to impairment of function. The contribution of impaired smooth muscle function has not been explored. We have obtained preliminary evidence that high glucose levels induce specific changes in the expression of signaling targets (RGS4; CPI-17) mediating initial Ca2+-dependent contraction and sustained Ca2+-independent contraction. The changes augmented contraction in gastric smooth muscle from diabetic ob/ob mice and in control smooth muscle treated for 48 h with high glucose. Downregulation of RGS4 reduced inactivation of Gaq and augmented initial contraction. Upregulation of CPI-17 increased inhibition of MLC phosphatase via the PKC/CPI-17 pathways and augmented sustained contraction. We have now identified two microRNAs (miRs) whose expression is driven by high glucose that specifically regulate RGS4 (miR-1), and CPI-17 (miR-145) and have obtained preliminary evidence that high levels of reactive oxygen species (ROS) generated by increased glucose flux in mitochondria and via alternative glucose metabolic pathways (glucosamine, polyol, and glyceraldehyde-3-P) mediate the changes in miR expression, which, in turn, regulate the expression of signaling targets. The effects of high glucose on (a) the expression of miRs and signaling targets, (b) the activity of downstream effectors, and (c) the increase in contraction were reversed by the antioxidant, N-acetyl cysteine. The Specific Aims of this proposal are as follows: (1) Establish ROS as the link between high glucose levels and microRNA regulators (miR-1, miR-145) of signaling targets (RGS4, CPI-17) that mediate initial and sustained contraction in gastric smooth muscle from ob/ob mice and in control smooth muscle treated with high glucose. (2) Characterize the regulation of RGS4 expression by miR-1, and using selective agomirs and antagomirs to define its contribution to changes in signaling via the RGS4/Gaq/PLC-?1/IP3/Ca2+/MLC kinase/MLC20 cascade and CPI-17 expression by miR-145 and define their contribution to signaling via the PKC/CPI-17/MLCP pathways. The results from our studies have the potential to give novel insights and strategies in the development and treatment of gastric motility dysfunction in diabetes. These funds will be used to increase our understanding and develop further focused extensive investigations utilizing NIH R01 funding.
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Oxidative Stress, microRNA, and Hyper-Contractility in Diabetes (Mahavadi, Sunila)
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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 Gastro-Intestinal (GI) Committee has the principal function of furthering the mission of the consortium with regard to diabetic gastro-intestinal (GI) and liver 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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