The overall objective of this study is to determine whether systemic inflammation in diabetes and obesity persists because of a failure of endogenous pathways that normally resolve inflammation. Our working hypothesis is that chronic inflammation in T2D and obesity is sustained in part due to a deficiency in specialized pro-resolving lipid mediator (SPM)-stimulated resolution, which impairs wound healing. To test this hypothesis, we will assess the development and resolution of acute inflammation in wild type and obese-diabetic mice and determine how SPM pathways are affected by nutrient excess. We will also perform a targeted lipidomic analysis of adipose tissue and plasma obtained from obese diabetic and non-diabetic humans undergoing bariatric surgery to elucidate whether SPM biosynthesis is associated with inflammation and metabolic parameters. Utilizing these approaches, we will be able to elucidate how diabetes impacts resolution of inflammation and determine how SPM pathways are modulated in obese and diabetic humans. Lastly, to test the efficacy of SPM in treating clinically-relevant manifestations of diabetes, we will determine whether promoting resolution will decrease inflammation and enhance wound healing in a rodent model of cutaneous wound healing. We expect that this project will generate new knowledge regarding the mechanisms that sustain chronic inflammation in T2D and move the field forward by testing the efficacy of SPM in preventing not just systemic insulin resistance, bu also specific clinical manifestations of diabetes such as impaired wound healing. In addition, these studies will determine the association between insulin resistance and SPM pathways in obese humans, which has not been previously assessed. Completion of these translational studies will lead to a better understanding of the mechanisms that sustain chronic inflammation in obesity and diabetes;an understanding that will open up new avenues for exploring a novel set of therapies for attenuating inflammation and promoting wound healing in diabetic patients.
Results of this project will provide a new understanding of the mechanistic basis whereby diabetics suffer from delayed wound healing and chronic inflammation. These studies could lead to the development of new therapeutics aimed at resolving inflammation.
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|Fredman, Gabrielle; Hellmann, Jason; Proto, Jonathan D et al. (2016) An imbalance between specialized pro-resolving lipid mediators and pro-inflammatory leukotrienes promotes instability of atherosclerotic plaques. Nat Commun 7:12859|
|Zhang, Michael J; Sansbury, Brian E; Hellmann, Jason et al. (2016) Resolvin D2 Enhances Postischemic Revascularization While Resolving Inflammation. Circulation 134:666-680|
|Hellmann, Jason; Sansbury, Brian E; Holden, Candice R et al. (2016) CCR7 Maintains Nonresolving Lymph Node and Adipose Inflammation in Obesity. Diabetes 65:2268-81|
|Grenon, S Marlene; Owens, Christopher D; Nosova, Emily V et al. (2015) Short-Term, High-Dose Fish Oil Supplementation Increases the Production of Omega-3 Fatty Acid-Derived Mediators in Patients With Peripheral Artery Disease (the OMEGA-PAD I Trial). J Am Heart Assoc 4:e002034|
|Hellmann, Jason; Tang, Yunan; Zhang, Michael J et al. (2015) Atf3 negatively regulates Ptgs2/Cox2 expression during acute inflammation. Prostaglandins Other Lipid Mediat 116-117:49-56|
|Cummins, Timothy D; Holden, Candice R; Sansbury, Brian E et al. (2014) Metabolic remodeling of white adipose tissue in obesity. Am J Physiol Endocrinol Metab 307:E262-77|
|Billeter, Adrian T; Hellmann, Jason; Roberts, Henry et al. (2014) MicroRNA-155 potentiates the inflammatory response in hypothermia by suppressing IL-10 production. FASEB J 28:5322-36|
|Fredman, Gabrielle; Ozcan, Lale; Spolitu, Stefano et al. (2014) Resolvin D1 limits 5-lipoxygenase nuclear localization and leukotriene B4 synthesis by inhibiting a calcium-activated kinase pathway. Proc Natl Acad Sci U S A 111:14530-5|
|Tang, Yunan; Zhang, Michael J; Hellmann, Jason et al. (2013) Proresolution therapy for the treatment of delayed healing of diabetic wounds. Diabetes 62:618-27|
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