Nutrient excess alters resolution of inflammation in diabetes and obesity

营养过剩会改变糖尿病和肥胖症炎症的消退

• 批准号: 8883873
• 负责人: Jason L Hellmann
• 金额: $ 3.04万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8883873
• 关键词: Acute; Adipose tissue; Affect; Anabolism; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Apoptotic; Atherosclerosis; Attenuated; Blood Vessels; Cells; Centers for Disease Control and Prevention (U.S.); Chronic; Clinical; Cutaneous; Defect; Development; Diabetes Mellitus; Diabetic mouse; Diet; Epidemic; Event; Explosion; Failure; Fibrosis; Healed; Health; Homeostasis; Human; Hyperglycemia; Immune response; Immunosuppression; Impaired wound healing; Infection; Infiltration; Inflammation; Inflammatory; Injury; Insulin Resistance; Interruption; Intervention; Knowledge; Lead; Leukocytes; Liquid Chromatography; Measures; Mediating; Mediator of activation protein; Metabolic; Microbe; Molecular; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obesity; Omega-3 Fatty Acids; Pathway interactions; Patients; Peritoneal; Phagocytes; Phagocytosis; Phase; Physiological; Plasma; Population; Process; Public Health; Recurrence; Resolution; Retinal Diseases; Risk; Rodent Model; Testing; Time; Tissue Expansion; Tissues; Work; Wound Healing; Zymosan; bariatric surgery; base; clinical application; clinically relevant; db/db mouse; diabetic; diabetic patient; efficacy testing; healing; improved; insulin sensitivity; lipid mediator; liquid chromatography mass spectrometry; macrophage; microbial; non-diabetic; novel; novel therapeutics; peripheral blood; prevent; response; tandem mass spectrometry; tissue regeneration; tissue repair; translational study

DESCRIPTION (provided by applicant): The overall objective of this study is to determine whether systemic inflammation in diabetes and obesity persists because of a failure of endogenous pathways that normally resolve inflammation. Our working hypothesis is that chronic inflammation in T2D and obesity is sustained in part due to a deficiency in specialized pro-resolving lipid mediator (SPM)-stimulated resolution, which impairs wound healing. To test this hypothesis, we will assess the development and resolution of acute inflammation in wild type and obese-diabetic mice and determine how SPM pathways are affected by nutrient excess. We will also perform a targeted lipidomic analysis of adipose tissue and plasma obtained from obese diabetic and non-diabetic humans undergoing bariatric surgery to elucidate whether SPM biosynthesis is associated with inflammation and metabolic parameters. Utilizing these approaches, we will be able to elucidate how diabetes impacts resolution of inflammation and determine how SPM pathways are modulated in obese and diabetic humans. Lastly, to test the efficacy of SPM in treating clinically-relevant manifestations of diabetes, we will determine whether promoting resolution will decrease inflammation and enhance wound healing in a rodent model of cutaneous wound healing. We expect that this project will generate new knowledge regarding the mechanisms that sustain chronic inflammation in T2D and move the field forward by testing the efficacy of SPM in preventing not just systemic insulin resistance, bu also specific clinical manifestations of diabetes such as impaired wound healing. In addition, these studies will determine the association between insulin resistance and SPM pathways in obese humans, which has not been previously assessed. Completion of these translational studies will lead to a better understanding of the mechanisms that sustain chronic inflammation in obesity and diabetes; an understanding that will open up new avenues for exploring a novel set of therapies for attenuating inflammation and promoting wound healing in diabetic patients.

描述（由申请人提供）：本研究的总体目标是确定糖尿病和肥胖症的全体性炎症是否由于通常解决炎症的内源性途径失败而持续存在。我们的工作假设是，T2D和肥胖的慢性炎症持续的部分原因是缺乏专门的促溶解脂质介质（SPM）刺激的溶解，这损害了伤口愈合。为了验证这一假设，我们将评估野生型和肥胖糖尿病小鼠急性炎症的发展和消退，并确定营养过剩如何影响SPM途径。我们还将对接受减肥手术的肥胖糖尿病患者和非糖尿病患者的脂肪组织和血浆进行针对性的脂质组学分析，以阐明SPM生物合成是否与炎症和代谢参数相关。利用这些方法，我们将能够阐明糖尿病如何影响炎症的消退，并确定肥胖和糖尿病患者如何调节SPM通路。最后，为了测试SPM治疗糖尿病临床相关表现的疗效，我们将在啮齿动物皮肤伤口愈合模型中确定促进消退是否会减少炎症并促进伤口愈合。我们期望这个项目将产生关于维持t2dm慢性炎症机制的新知识，并通过测试SPM在预防全身胰岛素抵抗以及糖尿病的特定临床表现（如伤口愈合受损）方面的功效，推动该领域向前发展。此外，这些研究将确定肥胖人群中胰岛素抵抗和SPM通路之间的关系，这在以前没有被评估过。这些转化研究的完成将有助于更好地理解肥胖和糖尿病中慢性炎症的维持机制；这一认识将为探索糖尿病患者减轻炎症和促进伤口愈合的一套新疗法开辟新的途径。