Dendritic cells in immuno-metabolic disorder in mouse and man

描述（由申请人提供）：该提案解决了我们对树突状细胞和先天免疫在免疫代谢功能障碍中的作用的认识和理解中的一个重要空白。越来越多的证据表明，肥胖和肥胖诱导的2型糖尿病（T2 D）在很大程度上是一种由先天免疫和适应性免疫介导的炎症性疾病。在细胞水平，众所周知，命名为M1的炎性巨噬细胞在肥胖和相关代谢并发症（包括T2 D）过程中的脂肪组织低度炎症中发挥重要作用。在脂肪组织中还发现T淋巴细胞（CD 4+、CD 8+和Foxp 3 + Treg）和B细胞，并且浸润水平与肥胖和代谢功能障碍的严重程度相关。树突状细胞是连接先天性和适应性免疫应答的核心，通过MyD 88等信号传导的受体应答，以刺激适应性免疫应答。这些细胞在适应性免疫T和B细胞的上游发挥关键作用，并在免疫应答的早期阶段与巨噬细胞相互作用。然而，关于树突状细胞（DCs）在肥胖及其并发症T2 D的免疫发病机制中的作用以及MyD 88的作用知之甚少，MyD 88是一种重要的衔接蛋白，其控制这些代谢疾病中的先天免疫。本申请旨在解决肥胖和相关T2 D动物模型以及患有这些疾病的患者中的这一问题。这将通过使用DC中MyD 88的“功能获得”和“功能丧失”的独特小鼠模型系统以及在经历胃旁路手术的肥胖和/或T2 D患者中的研究来实现。我们的研究将通过主要研究者、共同主要研究者和合作者之间的密切合作来实现，他们都是经验丰富的研究者，具有独特的能力，能够将基础和临床科学以及免疫生物学和糖尿病/代谢领域联系起来。

DESCRIPTION (provided by applicant): This proposal addresses an important gap in our knowledge and understanding of the role of dendritic cells and innate immunity in immuno-metabolic dysfunction. Increasing evidence indicates that obesity and obesity-induced type 2 diabetes (T2D) is, in large part an inflammatory disorder mediated by both innate and adaptive immunity. At the cellular level, it is well recognized that inflammatory macrophages, designated as M1, play an important role in the low-grade inflammation in adipose tissue during the course of obesity and related metabolic complications including T2D. T lymphocytes, (CD4+, CD8+ and Foxp3+ Treg) and B cells are also found in the adipose tissue and the level of infiltration is correlated with the severity of obesity and metabolic dysfunction. Dendritic cells are central to linking innate and adaptive immune responses, responding through receptors that signal through MyD88, amongst others, to stimulate adaptive immune responses. These cells play a key role upstream of the adaptive immune T and B cells as well as interact with macrophages in early phases of the immune response. However, not much is known about the role of dendritic cells (DCs) in the immunopathogenesis of obesity and its complication T2D and the role of MyD88, an important adaptor protein that controls innate immunity in these metabolic disorders. The current application is designed to address this issue in both animal models of obesity and related T2D as well as patients with these disorders. This will be achieved by using a unique mouse model system of both "gain-of-function" and "loss-of-function" of MyD88 in DCs and the studies in patients with obesity and/or T2D who undergo gastric bypass surgery. Our study will be achieved by a close collaboration between the principal investigator, the co-PI and the collaborator, who are experienced investigators with the unique capacity to bridge basic and clinical science as well as the fields of immunobiology and diabetes/metabolism.