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

• 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
• 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

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（T2 D）与炎症反应的慢性激活有关，炎症反应在组织功能障碍和代谢改变中起因果作用。特别是骨骼肌，是胰岛素作用的主要部位，并且随着肥胖和T2 D的进展而变得发炎和胰岛素抵抗，最终导致异位脂质沉积和萎缩。与非糖尿病患者相比，患有T2 D的个体随着年龄的增长表现出肌肉质量和力量的加速损失。作为疾病过程的结果，肥胖和T2 D改变对损伤的反应，使得正常组织修复反应受损并导致纤维化。事实上，正常组织修复反应的扰动是T2 D最突出的继发性并发症之一。增加饮食中的omega-3 PUFA或直接给予消退素可缓解炎症并改善糖尿病的全身代谢。我们最近发现，在肌肉损伤和再生过程中，从促炎性到促消退性脂质介质（resolvins）的时间转变称为脂质介质类别转换。我们发现，resolvin D2（RvD 2）可以减少炎症，加速肌肉再生和功能的恢复。尽管如此，这些有益效果背后的具体机制还不完全清楚。消退素及其ω-3 PUFA前体，特别是如果在饮食中提供，在代谢疾病的背景下，在肌肉损伤恢复期间的作用尚未评估。重要的是，从糖尿病肌肉中获得的初步脂质介质概况表明损伤和再生期间脂质介质类别转换受损。我们建议全面研究营养性omega-3 PUFA摄入、脂质介质产生、炎症消退、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受到干扰，以及靶向消退素治疗是否比欧米茄-3 PUFA营养干预更有效。我们的研究将扩大我们对omega-3 PUFA与RvD 2在解决慢性炎症和促进组织修复方面的比较功效的理解。他们可以发现在代谢疾病中omega-3 PUFA的利用是否存在改变，这可以为omega-3 PUFA的进一步临床研究以及个性化医疗提供信息。