Role of CD40 in Obesity-Induced Adipose Tissue Inflammation & Insulin Resistance

描述（由申请人提供）：肥胖诱导的炎症是胰岛素抵抗和2型糖尿病发病机制的一个促成因素。脂肪组织巨噬细胞（ATM）和脂肪组织T细胞（ATT）在肥胖期间积聚。ATM和ATT产生损害脂肪组织中胰岛素作用的促炎信号。然而，对ATT和ATM如何通信以启动和维持脂肪组织炎症并在肥胖期间产生胰岛素抵抗缺乏明确的理解。我们的研究小组正在探索这样一个假设，即脂肪组织中ATM和ATT之间的通信是塑造脂肪中炎症环境的核心。我们已经发现，在饮食诱导的肥胖期间，内脏脂肪中的CD 40表达增加，并且ATM表达CD 40。CD 40是属于TNF受体超家族的跨膜糖蛋白。CD 40的配体CD 40 L（或CD 154）在活化的T淋巴细胞上高度表达。已经显示CD 40-CD 40 L信号传导对于T细胞引发、效应子功能和T细胞介导的免疫的起始是关键的。我们的初步数据支持一个模型，其中来自高脂肪饮食暴露的信号诱导ATM上的CD 40，以促进CD 4 + ATT的活化和扩增。本申请的中心假设是，CD 40-CD 40 L途径介导ATM和ATT之间的通信，以促进ATM活化，从而驱动抗原特异性CD 4 + ATT的扩增并诱导肥胖期间的炎症和胰岛素抵抗。本培训计划的目标是让学员严格测试该模型，同时学习和应用免疫学技术来测量培养细胞和脂肪中的ATM功能和ATT反应。在目标1中，我们将确定如何CD 40的表达在ATM是由脂肪细胞调节。具体来说，我们将测试工作假设，即脂肪细胞肥大和死亡激活TLR 4和NF-：B信号通路在ATM诱导CD 40的表达。在目标2中，我们将研究CD 40活化对M1和M2 ATM生物学的影响。所提出的实验将测试CD 40活化是否通过ATM诱导成熟和细胞因子产生，以及CD 40活化是否参与ATM对ATT的调节。在目标3中，我们将测试工作假设，即白细胞中的CD 40活化是肥胖期间内脏脂肪中炎症信号产生的主要原因。所提出的实验将提供关于CD 40-CD 40 L信号传导是否以及如何有助于肥胖诱导的炎症的清楚理解。该培训计划是专门为促进免疫学和代谢领域的交叉培训而设计的。培训生将发展ATM生物学和肥胖诱导炎症调节方面的专业知识，学习与ATM和ATT调节相关的关键免疫学概念，并接受免疫学家和肥胖研究人员使用的最先进技术的培训。

DESCRIPTION (provided by applicant): Obesity-induced inflammation is a contributing factor in the pathogenesis of insulin resistance and Type 2 diabetes. Both adipose tissue macrophages (ATMs) and adipose tissue T cells (ATTs) accumulate during obesity. ATMs and ATTs produce pro-inflammatory signals that impair insulin action in adipose tissue. However, a clear understanding of how ATTs and ATMs communicate to initiate and sustain adipose tissue inflammation and generate insulin resistance during obesity is lacking. Our group is exploring the hypothesis that communication between ATMs and ATTs in adipose tissue is central to shaping the inflammatory environment in fat. We have found that CD40 expression is increased in visceral fat during diet-induced obesity and that ATMs express CD40. CD40 is a transmembrane glycoprotein belonging to the TNF receptor superfamily. The ligand for CD40, CD40L (or CD154), is highly expressed on activated T lymphocytes. CD40- CD40L signaling has been shown to be critical for T cell priming, effector function, and initiation of T cell- mediated immunity. Our preliminary data support a model in which signals derived from high fat diet exposure induce CD40 on ATMs to promote activation and expansion of CD4+ ATTs. The central hypothesis of this application is that the CD40-CD40L pathway mediates communication between ATMs and ATTs to promote ATM activation to drive expansion of antigen-specific CD4+ ATTs and induce inflammation and insulin resistance during obesity. The goal of this training proposal is for the trainee to rigorously test this model while learning and applying immunology techniques to measure ATM function and ATT responses in cultured cells and in fat. In Aim 1, we will determine how CD40 expression in ATMs is regulated by adipocytes. Specifically, we will test the working hypothesis that adipocyte hypertrophy and death activates TLR4 and NF-:B signaling pathways in ATMs to induce CD40 expression. In Aim 2, we will examine the effects of CD40 activation on the biology of M1 and M2 ATMs. The proposed experiments will test whether CD40 activation induced maturation and cytokine production by ATMs, and whether CD40 activation participates in the regulation of ATTs by ATMs. In Aim 3, we will test the working hypothesis that CD40 activation in leukocytes is principally responsible for the generation of inflammatory signals in visceral fat during obesity. The proposed experiments will provide a clear understanding as to whether and how CD40-CD40L signaling contributes to obesity- induced inflammation. The training proposal is specifically designed to promote cross training in the fields of immunology and metabolism. The trainee will develop expertise in ATM biology and regulation of obesity- induced inflammation, learn key immunological concepts relevant to the regulation of ATMs and ATTs, and receive training in state of the art techniques used by immunologists and obesity researchers.