Role of Cytokine-Induced Inflammation in Endothelial Dysfunction in Diabetes

细胞因子诱导的炎症在糖尿病内皮功能障碍中的作用

基本信息

批准号：
8828272
负责人：
Michael A HILL
金额：
$ 36.8万
依托单位：
UNIVERSITY OF MISSOURI-COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-02-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8828272
关键词：
Ablation Affect Aftercare Antigens Blood Vessels CD4 Positive T Lymphocytes Cells Coronary DNA Dendritic Cells Dendritic cell activation Development Diabetes Mellitus Diabetic Angiopathies Diabetic mouse Diphtheria Toxin Disease Electron Spin Resonance Spectroscopy Elements Endothelium Event Fluorescence Microscopy Functional disorder Funding Genetic Goals Heart Diseases Human ITGAM gene ITGAX gene Immune Impairment In Vitro Inflammation Inflammatory Injury Interferon Type II Knockout Mice Knowledge Lead Link Macrophage Activation Mediating Microcirculation Microvascular Dysfunction Modeling Morbidity - disease rate Mus Mutation Myocardial Ischemia Natural Immunity Nitric Oxide Non-Insulin-Dependent Diabetes Mellitus Outcome Oxidative Stress Play Population Production Proteins RNA Receptor Activation Research Personnel Risk Factors Role Smooth Muscle Myocytes Societies Stroke Superoxides T-Cell Activation T-Cell Development T-Lymphocyte Testing Therapeutic Toxin Tumor Necrosis Factor-alpha Tunica Adventitia Vascular Diseases Vasodilator Agents Western Blotting Work arteriole cell type combat cytokine db/db mouse design diabetes risk diabetic diabetic cardiomyopathy diphtheria toxin receptor endothelial dysfunction experience improved insight macrophage monocyte mortality mouse model neutralizing antibody nitration novel novel strategies prevent promoter research study response targeted treatment therapeutic development therapy design vascular inflammation

项目摘要

DESCRIPTION (provided by applicant): The overarching goal of this proposal is to test the central hypothesis that: coronary dysfunction in type 2 diabetic mice is produced by the activation of dendritic cells (DC) with subsequent expression of interferon gamma (IFN). There are 3 specific aims and each aim has 2 hypotheses. The first aim will causally determine the role of dendritic cell (DC) activation in endothelial dysfunction in coronary arterioles in type 2 diabetes. We propose that 1) Endothelial function will be preserved in coronary arterioles in a cross between type 2 diabetic (db/db) and CD11c-DTR mice, a mouse "conditionally null" for DC. In this model, DCs are depleted after treatment with Diptheria toxin and comparisons will be made to both littermate controls (lean Db/db or wild type [WT], but conditionally null for DC) or mice not treated with Diptheria toxin (and thus containing the resident population of DCs); and 2) Levels of inflammatory cytokines (interferon gamma IFN and TNF) will be reduced in db/db x CD11c-DTR following treatment with Diptheria toxin and comparable to lean littermates, Db/db or WT x CD11c-DTR; and 3) In diabetic mice depleted of DCs (db/db x CD11c-DTR), activation of T cells and macrophages are reduced compared to db/db mice and comparable to lean littermates, Db/db or WT x CD11c-DTR. The second aim will determine if activation of DCs progresses to activation of T cells and macrophages leading to release of the inflammatory cytokines in coronary arterioles in type 2 diabetes. We propose that in a diabetic model with genetic deletion of T cells (db/db x CD4+ -/-; this is a mouse model on a C57BL/6 background with a targeted mutation in Cd4tm1Mak that significantly blocks in CD4+ T-cell development) endothelium-dependent vasodilatory responses are greater, and markers of oxidative stress (superoxide production, protein nitration) are reduced, compared to that in type 2 diabetic db/db mice. Vasodilatory responses of db/db x CD4+ -/- will be comparable to that of littermate, lean control (Db/db x CD4+ -/-) mice. We also propose that in a diabetic model with Diptheria toxin induced deletion of macrophages (db/db x CD11b-DTR; this is a mouse model which expresses the human diphtheria toxin receptor [DTR] under the control of the CD11b promoter. Treatment with diphtheria toxin results in the complete ablation of circulating monocytes), endothelium-dependent vasodilatory responses are greater, and markers of oxidative stress (superoxide production, protein nitration) are reduced, compared to that in type 2 diabetic db/db mice. Responses of db/db x CD11b-DTR will be comparable to that in the littermate, lean control (Db/db x CD11b-DTR) mice. We will use a combination of methodological approaches principally consisting of in vitro microscopy, fluorescence and electron paramagnetic resonance (EPR) analysis of superoxide (O2¿¿) production, real timePCRfor RNA and DNA analyse s, and Western Blotting to evaluate expression of key proteins in all strains and crosses. We believe that this study will provide a new understanding of, and new approaches for, the treatment of vascular injury in type 2 diabetes and related disorders/complications. This work will increase our knowledge of the role of dendritic cells, T cells and macrophage-induced vascular inflammation, which causes vascular dysfunction in type 2 diabetes. These studies will aid development of therapeutic strategies by providing results that hone our understanding of how DC activation affects coronary impairment and improve how we develop optimal therapeutic strategies for harnessing the adaptive impact of latent, innate immunity to combat inflammation.

描述（由应用程序提供）：该提案的总体目标是测试中心假设：2型糖尿病小鼠中的冠状动脉功能障碍是由树突细胞（DC）激活并随后表达干扰素伽马（IFN）产生的。有3个特定目标，每个目标都有2个假设。第一个目标将有可能确定树突状细胞（DC）激活在2型糖尿病中冠状动脉动脉内皮功能障碍中的作用。我们建议1）在2型糖尿病（DB/DB）和CD11C-DTR小鼠之间的十字架中，内皮功能将保存在冠状动脉art中，这是DC的小鼠“有条件无效”。在该模型中，DC在用白喉毒素治疗后会耗尽，并进行比较与同窝窝对照（瘦的db/db或野生型[wt]，但对于DC的有条件为无效）或未用白喉毒素处理的小鼠（因此包含居民的炎症和2级）（如果含有较高的cyma）（Intry and and Intermant）（Intry and and Intry）。 DB/DB X CD11C-DTR用白喉毒素处理后，与瘦同杂的同窝，db/db或wt x cd11c-dtr相当； 3）在DCS（DB/DB X CD11C-DTR）中耗尽的糖尿病小鼠中，与DB/DB小鼠相比，T细胞和巨噬细胞的激活减少，并且与瘦同窝仔，DB/DB或WT X x CD11C-DTR相当。第二个目的将确定DCS的激活是否发展为T细胞和巨噬细胞的激活，导致2型糖尿病中冠状动脉动脉中炎性细胞因子的释放。我们提出，在具有T细胞遗传缺失的糖尿病模型中（DB/DB X CD4+ - / - ；这是CD4TM1MAK中具有靶向突变的小鼠模型，在CD4+ T-Cell发育中显着阻碍了依赖于依赖于氧化的cd4tm1mak的靶向突变，它依赖于氧化剂的血管疾病响应量更大（依赖于氧化）。在2型糖尿病DB/DB小鼠中。 db/db x cd4+ - / - 的血管舒张反应将与窝窝控制，瘦肉控制（db/db x cd4+ - / - ）小鼠相当。 We also propose that in a diabetic model with Diptheria toxin induced deletion of macrophages (db/db x CD11b-DTR; this is a mouse model which expresses the human diphtheria toxin receptor [DTR] under the control of the CD11b promoter. Treatment with diphtheria toxin results in the complete ablation of circulating monocytes, endothelium-dependent vasodilatory responses与2型糖尿病DB/dB小鼠相比，氧化应激的标记（超氧化物产生，蛋白质硝化）是相比的。对超氧化物的产生（O2€）的电子磁共振共鸣（EPR）分析，REALPCRFOR RNA和DNA分析s和Western印迹，以评估所有菌株和十字架中关键蛋白的表达这项工作将增加我们对树突状细胞，T细胞和巨噬细胞诱导的血管感染的作用的了解，这会导致2型糖尿病中的血管功能障碍。这些研究将通过提供结果来帮助制定理论策略的发展，使我们对DC激活如何影响冠状动脉损害的理解，并改善我们如何制定最佳治疗策略来利用潜在的，先天免疫学对抗击炎症的适应性影响。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Advanced glycation end products acutely impair ca(2+) signaling in bovine aortic endothelial cells.

晚期糖基化终末产物会严重损害牛主动脉内皮细胞中的 ca(2) 信号传导。

DOI：
10.3389/fphys.2013.00038
发表时间：
2013
期刊：
Frontiers in physiology
影响因子：
4
作者：
Naser,Nadim;Januszewski,AndrzejS;Brown,BronwynE;Jenkins,AliciaJ;Hill,MichaelA;Murphy,TimothyV
通讯作者：
Murphy,TimothyV

Diabetic Vasculopathy: Molecular Mechanisms and Clinical Insights.

DOI：
10.3390/ijms25020804
发表时间：
2024-01-09
期刊：
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
影响因子：
5.6
作者：
Jia, George;Bai, Hetty;Mather, Bethany;Hill, Michael A.;Jia, Guanghong;Sowers, James R.
通讯作者：
Sowers, James R.

Depletion of dendritic cells in perivascular adipose tissue improves arterial relaxation responses in type 2 diabetic mice.