Nutrient excess alters resolution of inflammation in diabetes and obesity

描述（由申请方提供）：本研究的总体目的是确定糖尿病和肥胖症中的全身性炎症是否由于通常解决炎症的内源性途径失效而持续存在。我们的工作假设是，T2 D和肥胖中的慢性炎症持续存在，部分原因是缺乏专门的促消退脂质介质（SPM）刺激的消退，这会损害伤口愈合。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解决，并确定SPM途径如何受到营养过剩的影响。我们还将对接受减肥手术的肥胖糖尿病和非糖尿病患者的脂肪组织和血浆进行靶向脂质组学分析，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SPM通路如何在肥胖和糖尿病患者中调节。最后，为了测试SPM在治疗糖尿病的临床相关表现中的功效，我们将确定促进消退是否会在皮肤伤口愈合的啮齿动物模型中减少炎症并增强伤口愈合。我们期望该项目将产生关于T2 D中维持慢性炎症的机制的新知识，并通过测试SPM在预防全身性胰岛素抵抗以及糖尿病的特定临床表现（如伤口愈合受损）方面的功效来推动该领域的发展。此外，这些研究将确定肥胖人群中胰岛素抵抗和SPM通路之间的关联，这在以前没有被评估过。这些转化研究的完成将使人们更好地理解肥胖和糖尿病患者慢性炎症的维持机制;这一理解将为探索一套减轻炎症和促进糖尿病患者伤口愈合的新疗法开辟新的途径。

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.