DHA-derived resolvin production andsignaling in tissue repair macrophages in metabolic disease

代谢疾病中组织修复巨噬细胞中 DHA 衍生的分解素的产生和信号传导

基本信息

批准号：
10357797
负责人：
Laszlo Nagy
金额：
$ 57.97万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-02 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10357797
关键词：
Adoptive Transfer Age Aging Anabolism Animal Model Anti-Inflammatory Agents Atrophic Biological Cardiovascular Diseases Cells Chemicals Chronic Clinical Research Deposition Diabetes Mellitus Diabetic mouse Dichloromethylene Diphosphonate Diet Dietary Intervention Direct Lytic Factors Disease Dopamine D2 Receptor Energy Intake Epidemic Essential Fatty Acids Exercise Exhibits Fibrosis Functional disorder GPR18 receptor Genes Genetic Host Defense ITGAM gene Immune Immunoglobulin Class Switching Immunosuppression Impairment Individual Inflammation Inflammatory Inflammatory Response Injury Insulin Insulin Resistance Intake Interruption Knockout Mice Lead Lipids Liposomes Mediating Mediator of activation protein Metabolic Metabolic Diseases Metabolism Modeling Mus Muscle Muscle function Muscular Atrophy Myelogenous Natural regeneration Necrosis Non-Insulin-Dependent Diabetes Mellitus Normal tissue morphology Nutritional Obesity Omega-3 Fatty Acids Pathway interactions Phagocytes Pharmaceutical Preparations Phenotype Play Process Production Recovery Regulation Resolution Role Signal Transduction Site Skeletal Muscle Source Testing Therapeutic Time Tissues cancer cachexia cellular targeting comparative efficacy db/db mouse diabetic human model improved in vivo insight lipid mediator lipidomics macrophage migration monocyte mouse model muscle form muscle regeneration muscle strength non-diabetic novel strategies personalized medicine programs regeneration function repaired reparative process response response to injury targeted treatment tissue injury tissue regeneration tissue repair tissue-repair responses

项目摘要

Obesity and type 2 diabetes (T2D) are associated with chronic activation of inflammatory responses that play a causal role in tissue dysfunction and altered metabolism. Skeletal muscle in particular, is a major site of insulin action and becomes inflamed and insulin resistant with the progression of obesity and T2D, leading ultimately to ectopic lipid deposition and atrophy. Individuals with T2D exhibit accelerated loss of muscle mass and strength with age compared to non-diabetics. As a consequence of the disease process, obesity and T2D alter the response to injury such that the normal tissue reparative responses are impaired and lead to fibrosis. Indeed, perturbation of the normal tissue repair response is one of the most prominent secondary complications of T2D. Increasing omega-3 PUFA in the diet or direct administration of resolvins resolves inflammation and improves systemic metabolism in diabetes. We recently discovered a temporal shift from pro-inflammatory to pro-resolving lipid mediators (resolvins) during muscle injury and regeneration in a process termed lipid mediator class switching. We found that resolvin D2 (RvD2) decreases inflammation and hastens recovery of muscle regeneration and function. Nonetheless, the specific mechanisms underlying these beneficial effects are incompletely understood. The role of resolvins and their omega-3 PUFA precursors, particularly if provided in the diet, during recovery from muscle injury, in the context of metabolic disease has not been evaluated. Importantly, preliminary lipid mediator profiles obtained from diabetic muscles indicate an impairment in the lipid mediator class switching during injury and regeneration. We propose to comprehensively investigate the relationship between nutritional omega-3 PUFA intake, lipid mediator production, inflammation-resolution, macrophage signaling and function, and muscle regeneration. We will further determine how these pathways are perturbed in metabolic disease and whether targeted resolvin therapy is more efficacious than omega-3 PUFA nutritional interventions. Our studies will broaden our understanding about the comparative efficacy of omega-3 PUFA vs. RvD2 for resolving chronic inflammation and promoting tissue repair. They could uncover whether there are alterations in utilization of omega-3 PUFA in metabolic disease that could inform further clinical studies on omega-3 PUFA, as well as personalized medicine.

肥胖和2型糖尿病（T2D）与炎症反应的慢性激活有关，这些反应在组织功能障碍和代谢改变中起因果作用。尤其是骨骼肌是胰岛素作用的主要部位，随着肥胖和T2D的发展而发炎和胰岛素耐药性，最终导致异位脂质沉积和萎缩。与非糖尿病药物相比，具有T2D的个体随着年龄的增长而表现出加速的肌肉质量和力量。由于疾病过程，肥胖症和T2D改变了对损伤的反应，使得正常的组织修复反应受损并导致纤维化。实际上，正常组织修复反应的扰动是T2D最突出的次要并发症之一。在饮食中增加omega-3 PUFA或直接施用resolvins可以解决炎症并改善糖尿病的系统性代谢。最近，我们发现在肌肉损伤和再生过程中，在称为脂质介导器类切换过程中，从促炎性炎症到促脂质介质（Resolvins）的时间转变。我们发现Resolvin D2（RVD2）降低了炎症并加快肌肉再生和功能的恢复。尽管如此，这些有益效果的基本机制尚不完全理解。在代谢性疾病的背景下，溶质素及其omega-3 PUFA前体的作用，尤其是在饮食中提供的作用，特别是在饮食中提供的作用。重要的是，从糖尿病肌肉中获得的初步脂质介质轮廓表明脂质介体类别在损伤和再生过程中发生了损害。我们建议全面研究营养omega-3 PUFA摄入量，脂质介质产生，炎症 - 分辨率，巨噬细胞信号传导和功能以及肌肉再生之间的关系。我们将进一步确定这些途径在代谢疾病中如何干扰以及靶向溶质治疗是否比Omega-3 PUFA营养干预更有效。我们的研究将扩大我们对Omega-3 PUFA与RVD2在解决慢性炎症和促进组织修复方面的比较功效的理解。他们可以揭示在代谢疾病中使用omega-3 PUFA的利用情况，这是否可以为Omega-3 PUFA以及个性化医学提供进一步的临床研究。