RESOLUTION OF DIABETIC VASCULAR INFLAMMATION: ROLE OF LIPID MEDIATORS PROJ5

糖尿病血管炎症的解决：脂质介质的作用 PROJ5

• 批准号: 8360418
• 负责人: Matthew R Spite
• 金额: $ 18.68万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8360418
• 关键词: Acute; Affect; Anabolism; Blood Vessels; Chronic; Diabetes Mellitus; Diabetic mouse; Endothelial Cells; Fatty Acids; Functional disorder; Funding; Glucose; Grant; Hyperglycemia; Hyperinsulinism; Infiltration; Inflammation; Inflammatory; Injection of therapeutic agent; Insulin-Dependent Diabetes Mellitus; Leukocytes; Lipoxins; Measures; Mediator of activation protein; Modeling; Mus; National Center for Research Resources; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathway interactions; Peritonitis; Phase; Principal Investigator; Research; Research Design; Research Infrastructure; Resolution; Resources; Role; Signal Pathway; Source; Streptozocin; Testing; Time; United States National Institutes of Health; cost; db/db mouse; design; diabetic; indexing; intravital microscopy; lipid mediator; liquid chromatography mass spectrometry; microbial; non-diabetic; novel; prevent; restoration; type I and type II diabetes; vascular inflammation

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.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 项目5：糖尿病血管炎症的消退：脂质介质的作用 该项目的总体目标是更好地了解支持和维持糖尿病慢性低度血管炎症的机制，以及是否可以刺激炎症的消退阶段以预防糖尿病血管功能障碍。 我们的假设是，糖尿病期间的慢性血管炎症可能部分归因于内源性反调节脂质介质通路的损失，该通路促进炎症的消退。 因此，用合成的促消退脂质介质（如脂氧素和消退素）恢复这些缺陷可以促进与长期糖尿病相关的血管炎症的消退。设计了以下具体目标来检验这一新假设： 1.检查糖尿病急性炎症消退的变化。 为此，我们将测量白细胞浸润的强度和持续时间在小鼠模型中的微生物腹膜炎，我们已经定义了具体的决议指数。将在非糖尿病小鼠以及1型和2型糖尿病的鼠模型中研究炎症的时间过程。1型糖尿病将通过链脲佐菌素注射建立，并且对于研究2型糖尿病，将使用db/db小鼠。 这些模型之间的比较将有助于评估高血糖症和高胰岛素血症对炎症消退中糖尿病变化的贡献，并有助于理解糖尿病影响炎症消退的机制; 2.评估促消退脂质介质生物合成改变对糖尿病消退变化的贡献。 为了了解糖尿病如何影响消退，我们将使用靶向液相色谱/质谱法鉴定腹膜炎期间脂质介质生物合成的变化。 我们将确定在1型和2型糖尿病模型的腹膜炎时程中哪些脂质介质途径（促炎与促消退）受到影响。 此外，为了阐明糖尿病影响促消退脂质介质生物合成的机制，我们将测量它们的生物合成中间体并确定它们如何受到糖尿病的影响; 3.确定促消退脂质介质治疗是否可恢复糖尿病消退的变化。我们将确定外源性脂氧素和消退素治疗如何影响非糖尿病和糖尿病小鼠腹膜炎的消退。为了阐明这些介质影响炎症的机制，我们将通过活体显微镜检查它们对白细胞：内皮细胞相互作用的影响。为了阐明促消退脂质介质对抗糖尿病血管炎症的细胞机制，我们将研究脂氧素和消退素如何影响微血管内皮细胞中高糖和高脂肪酸诱导的信号通路。