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.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Exploratory Grants (P20)
Project #
5P20RR024489-04
Application #
8360418
Study Section
National Center for Research Resources Initial Review Group (RIRG)
Project Start
2011-07-01
Project End
2012-06-30
Budget Start
2011-07-01
Budget End
2012-06-30
Support Year
4
Fiscal Year
2011
Total Cost
$186,835
Indirect Cost
Name
University of Louisville
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
057588857
City
Louisville
State
KY
Country
United States
Zip Code
40292
Guo, Yiru; Wysoczynski, Marcin; Nong, Yibing et al. (2017) Repeated doses of cardiac mesenchymal cells are therapeutically superior to a single dose in mice with old myocardial infarction. Basic Res Cardiol 112:18
Klionsky, Daniel J (see original citation for additional authors) (2016) Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12:1-222
Salabei, Joshua K; Lorkiewicz, Pawel K; Mehra, Parul et al. (2016) Type 2 Diabetes Dysregulates Glucose Metabolism in Cardiac Progenitor Cells. J Biol Chem 291:13634-48
Dassanayaka, Sujith; Jones, Steven P (2015) Recent Developments in Heart Failure. Circ Res 117:e58-63
Brooks, Alan C; DeMartino, Angelica M; Brainard, Robert E et al. (2015) Induction of activating transcription factor 3 limits survival following infarct-induced heart failure in mice. Am J Physiol Heart Circ Physiol 309:H1326-35
Salabei, Joshua K; Lorkiewicz, Pawel K; Holden, Candice R et al. (2015) Glutamine Regulates Cardiac Progenitor Cell Metabolism and Proliferation. Stem Cells 33:2613-27
Salabei, Joshua K; Hill, Bradford G (2015) Autophagic regulation of smooth muscle cell biology. Redox Biol 4:97-103
Muthusamy, Senthilkumar; DeMartino, Angelica M; Watson, Lewis J et al. (2014) MicroRNA-539 is up-regulated in failing heart, and suppresses O-GlcNAcase expression. J Biol Chem 289:29665-76
Salabei, Joshua K; Gibb, Andrew A; Hill, Bradford G (2014) Comprehensive measurement of respiratory activity in permeabilized cells using extracellular flux analysis. Nat Protoc 9:421-38
Dassanayaka, Sujith; Jones, Steven P (2014) O-GlcNAc and the cardiovascular system. Pharmacol Ther 142:62-71

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