This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Project 5: Resolution of diabetic vascular inflammation: Role of lipid mediators The overall aim of this project is to develop a better understanding of the mechanisms that support and sustain chronic low-grade vascular inflammation in diabetes and whether the resolution phase of inflammation could be stimulated to prevent vascular dysfunction in diabetes. Our hypothesis is that chronic vascular inflammation during diabetes could be attributed, in part, to a loss in endogenous counter-regulatory lipid mediator pathways that promote the resolution of inflammation. It follows that restoration of these deficits with synthetic pro-resolving lipid mediators, such as the lipoxins and resolvins, could facilitate the resolution of vascular inflammation associated with long-term diabetes. The following specific aims were designed to test this novel hypothesis: 1. Examine diabetic changes in the resolution of acute inflammation. For this, we will measure the intensity and duration of leukocyte infiltration in a murine model of microbial peritonitis in which we have defined specific resolution indices. The time course of inflammation will be studied in non-diabetic mice and in murine models of both type 1 and type 2 diabetes. Type 1 diabetes will be established by streptozotocin injections and for studying type 2 diabetes, db/db mice will be used. Comparisons between these models will help in assessing the contribution of hyperglycemia and hyperinsulinemia to diabetic changes in the resolution of inflammation and in understanding the mechanism by which diabetes affects the resolution of inflammation; 2. Assess the contribution of altered pro-resolution lipid mediator biosynthesis to diabetic changes in resolution. To understand how diabetes affects resolution, we will identify changes in lipid mediator biosynthesis during peritonitis using targeted liquid chromatography/mass spectrometry. We will determine which lipid mediator pathways (pro-inflammatory vs. pro-resolution) are affected during the time course of peritonitis in models of both type 1 and type 2 diabetes. Moreover, to elucidate the mechanisms by which diabetes affects pro-resolution lipid mediator biosynthesis, we will measure their biosynthetic intermediates and determine how they are affected by diabetes;and 3. Determine whether treatment with pro-resolution lipid mediators restores diabetic changes in resolution. We will determine how treatment with exogenous lipoxins and resolvins affects the resolution of peritonitis in non-diabetic and diabetic mice. To delineate the mechanisms by which these mediators affect inflammation, we will examine their effects on leukocyte:endothelial interactions by intravital microscopy. To elcuidate the cellular mechanisms by which pro-resolution lipid mediators counter-act diabetic vascular inflammation, we will examine how lipoxins and resolvins affect high glucose and high fatty acid-induced signaling pathways in microvascular endothelial cells.
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