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：
10571690
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 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10571690
关键词：
Acceleration 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 Lipids Liposomes Macrophage Mediating Mediator 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 Proliferating 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 migration monocyte mouse model muscle form muscle regeneration muscle strength non-diabetic novel strategies personalized medicine programs 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，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，随着肥胖和 T2D 的进展，骨骼肌会发炎和产生胰岛素抵抗，最终导致异位脂质沉积和萎缩。与非糖尿病患者相比，2 型糖尿病患者随着年龄的增长，肌肉质量和力量会加速丧失。作为疾病过程的结果，肥胖和 T2D 改变了对损伤的反应，从而使正常组织的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 T2D 最突出的继发并发症之一。在饮食中增加 omega-3 PUFA 或直接施用消退素可以缓解炎症并改善糖尿病患者的全身代谢。我们最近发现，在肌肉损伤和再生过程中，从促炎脂质介质到促溶解脂质介质（分解素）的时间转变被称为脂质介质类别转换。我们发现 resolvin D2 (RvD2) 可减少炎症并加速肌肉再生和功能的恢复。尽管如此，这些有益作用背后的具体机制尚不完全清楚。在代谢疾病的背景下，消退素及其 omega-3 PUFA 前体的作用，特别是在饮食中提供时，在肌肉损伤恢复过程中的作用尚未得到评估。重要的是，从糖尿病肌肉获得的初步脂质介质谱表明损伤和再生过程中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 omega-3 PUFA 营养干预更有效。我们的研究将加深我们对 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 omega-3 PUFA 在代谢疾病中的利用是否发生变化，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。