Immunometabolic consequences of alcohol-induced mesenteric lymphatic dyshomeostasis

摘要 此Ruth L.Kirschstein NRSA F30应用程序的主要目的是为 为申请者的学术医疗生涯做好准备。申请者的大部分职业发展将来自 来自酒精共病相关研究的工作。酒精是美国人滥用最多的物质 大约四分之一的成年人酗酒和/或酗酒。慢性酒精 消耗还会破坏葡萄糖的动态平衡，并与胰岛素抵抗的发展有关。 免疫系统在脂肪组织和全身新陈代谢中扮演着全面而低调的角色。 通过一系列称为免疫新陈代谢的过程来监测和响应特定的代谢信号。 我们以前的研究结果表明，酒精导致的肠系膜淋巴渗漏和随后的 淋巴周围脂肪组织炎症可能是系统性红斑狼疮发生发展的主要事件。 慢性酒精使用中出现的免疫代谢失调。此前，我们的实验室已经证明了慢性 酒精性淋巴渗漏、CD3+、CD4+T细胞、fTregs、IL-6升高。我们的研究 研究还表明，长期饮酒会导致平台上胰岛素刺激的葡萄糖摄取减少。我们 推测淋巴管中的细胞或分子渗入平板会刺激fTreg的扩张和铅 以消除代谢失调。总而言之，已公布的和初步的数据支持这样一种假设 酒精处理动物的淋巴内容扰乱了平台免疫和代谢动态平衡 通过fTreg扩展。这项拟议的研究将使用多种技术来检验这一假设 使用三个特定的目标：(1)酒精处理动物的淋巴将在幼稚的平板上扩大FOXP3+fTregs 外植体通过IL33/ST2信号通路，(2)酒精诱导的fTreg扩增有助于代谢 (3)酒精性血小板代谢紊乱与全身 新陈代谢后果。拟议中的研究结果将为我们深入了解 酒精相关淋巴渗漏及其成分对血小板免疫细胞环境的影响 FTregs，有助于平台IR和潜在的系统性IR的发展。拥有一支强大的指导团队 致力于培养全面发展的内科科学家，完成拟议的培训计划将 确保申请者准备好开始学术医学的职业生涯。

Abstract The primary purpose of this Ruth L. Kirschstein NRSA F30 application is to provide the groundwork that will prepare the applicant for an academic medical career. Much of the applicant’s career development will come from work in alcohol comorbidity-related research. Alcohol is the most abused substance in the United States with about one-quarter of the adult population partaking in heavy and/or binge drinking. Chronic alcohol consumption also disrupts glucose homeostasis and is associated with the development of insulin resistance. The immune system plays a comprehensive and understated role in adipose tissue and systemic metabolism surveilling and responding to specific metabolic signals through a set of processes termed immunometabolism. Results from our previous studies suggest that alcohol-induced mesenteric lymphatic leakage and subsequent perilymphatic adipose tissue inflammation may be a primary event in the development of systemic immunometabolic dysregulation seen in chronic alcohol use. Previously our lab has demonstrated that chronic alcohol induced lymphatic leakage, increased CD3+ and CD4+ T cells, fTregs, and IL-6 in PLAT. Our studies have also shown that chronic alcohol led to decreased insulin-stimulated glucose uptake in PLAT. We speculate that cells or molecules leaking from lymphatic vessels into PLAT stimulate fTreg expansion and lead to PLAT metabolic dysregulation. Taken together, published and preliminary data support the hypothesis that lymph contents from alcohol-treated animals disrupt PLAT immune and metabolic homeostasis through fTreg expansion. The proposed study will employ a wide variety of techniques to test the hypothesis using three specific aims: (1) Lymph from alcohol-treated animals will expand FOXP3+ fTregs in naïve PLAT explants via IL33/ST2 signaling pathway, (2) alcohol-induced fTreg expansion contributes to metabolic dysregulation in PLAT, and (3) alcohol-induced PLAT metabolic dysregulation is associated with systemic metabolic consequences. Findings from the proposed studies will provide insight on the deleterious effects of alcohol-associated lymph leakage and how its constituents impact PLAT immune cell milieu, specifically fTregs, contributing to development of PLAT IR and potentially systemic IR. With a strong mentoring team committed to developing a well-rounded physician scientist, completion of the proposed training plan will ensure that the applicant is ready to embark on a career in academic medicine.