Immunometabolic consequences of alcohol-induced mesenteric lymphatic dyshomeostasis

摘要 这个Ruth L的主要目的。Kirschstein NRSA F30应用程序是为了提供基础， 为申请人的学术医学生涯做好准备。申请人的大部分职业发展将来自 来自酒精合并症相关研究的工作。酒精是美国滥用最严重的物质 大约四分之一的成年人酗酒和/或暴饮。慢性酒精 消耗也破坏葡萄糖体内平衡并与胰岛素抗性的发展有关。 免疫系统在脂肪组织和全身代谢中起着全面而低调的作用 通过一系列称为免疫代谢的过程来监视和响应特定的代谢信号。 我们以前的研究结果表明，酒精诱导的肠系膜淋巴漏和随后的淋巴结转移可能是一个重要的因素。 淋巴管外脂肪组织炎症可能是全身性淋巴结炎发生的主要事件。 慢性酒精使用中的免疫代谢失调。以前我们的实验室已经证明， 乙醇诱导淋巴漏，增加PLAT中的CD 3+和CD 4 + T细胞、fT细胞和IL-6。我们的研究 还表明长期饮酒导致PLAT中胰岛素刺激的葡萄糖摄取减少。我们 推测从淋巴管泄漏到PLAT中的细胞或分子刺激fTreg扩增并导致 PLAT代谢失调总之，已发表的和初步的数据支持这一假设， 酒精处理动物的淋巴内容物破坏PLAT免疫和代谢稳态 通过fTreg扩增。拟议的研究将采用各种各样的技术来检验这一假设 使用三个特定的目的：（1）酒精处理动物的淋巴液将在未处理PLAT中扩增FOXP 3 + fT 3 外植体通过IL 33/ST 2信号通路，（2）酒精诱导的fTreg扩增有助于代谢 PLAT代谢失调，（3）酒精诱导的PLAT代谢失调与全身性 代谢的后果。从拟议的研究结果将提供洞察的有害影响， 酒精相关的淋巴渗漏及其成分如何影响PLAT免疫细胞环境，特别是 通过强大的指导团队，为PLAT IR和潜在的系统IR的发展做出贡献。 致力于发展一个全面的医生科学家，完成拟议的培训计划将 确保申请人准备好开始学术医学生涯。

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.