Immunometabolic consequences of alcohol-induced mesenteric lymphatic dyshomeostasis

酒精引起的肠系膜淋巴稳态失调的免疫代谢后果

• 批准号: 10679999
• 负责人: Kourtney D Weaver
• 金额: $ 3.95万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10679999
• 关键词: Adipose tissue; Adult; Age; Alcohols; Animal Feed; Animals; Antigen-Presenting Cells; Antigens; Biochemical; CD3 Antigens; CD4 Positive T Lymphocytes; Cause of Death; Cell Separation; Cells; Chronic; Coculture Techniques; Consumption; Control Animal; Data; Dendritic Cells; Development; Diet; Ensure; Environment; Event; Extravasation; FOXP3 gene; Fatty acid glycerol esters; Fellowship; Future; Gastrointestinal tract structure; Glucose; Heavy Drinking; Histologic; Homeostasis; Immune; Immune system; Immunology; Inflammation; Insulin; Insulin Resistance; Interleukin-2; Interleukin-6; Lamina Propria; Life Style; Liver; Lymph; Lymphatic; Lymphatic System; Measures; Medical; Medicine; Mentors; Metabolic; Metabolism; Modeling; Mucous Membrane; Mus; National Research Service Awards; Natural Immunity; Nonesterified Fatty Acids; OGTT; Pathway interactions; Physicians; Play; Population; Process; Publishing; Rattus; Regulatory T-Lymphocyte; Reporting; Research; Role; Scientist; Signal Pathway; Signal Transduction; Stromal Cells; T-Lymphocyte; Techniques; Testing; Tissue Banks; Tissues; Tobacco; Training; Triglycerides; Unhealthy Diet; United States; Visceral; Work; adaptive immunity; adipokines; aged; alcohol comorbidity; alcohol consequences; alcohol content; alcohol effect; binge drinking; blood glucose regulation; career; career development; chronic alcohol ingestion; dietary control; glucose uptake; inflammatory milieu; insight; insulin sensitivity; insulin signaling; lipid metabolism; lymphatic vessel; macromolecule; mesenteric lymph node; mesenteric lymphatics; receptor; response; success; training opportunity

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.

抽象的 Ruth L. Kirschstein NRSA F30 应用程序的主要目的是提供基础工作， 为申请人的学术医学生涯做好准备。申请人的职业发展大部分将随之而来。 来自酒精合并症相关研究工作。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/或长期酗酒。 消耗也会破坏葡萄糖稳态，并与胰岛素抵抗的发展有关。 免疫系统在脂肪组织和全身代谢中发挥着全面而低调的作用 通过一系列称为免疫代谢的过程来调查和响应特定的代谢信号。 我们之前的研究结果表明，酒精引起的肠系膜淋巴漏和随后的 外淋巴脂肪组织炎症可能是全身性炎症发展的主要事件 此前我们的实验室已经证明，慢性饮酒会导致免疫代谢失调。 酒精诱导淋巴渗漏，增加 PLAT 中的 CD3+ 和 CD4+ T 细胞、fTreg 和 IL-6。 还表明，长期饮酒会导致 PLAT 中胰岛素刺激的葡萄糖摄取减少。 推测从淋巴管渗漏到 PLAT 的细胞或分子刺激 fTreg 扩张并导致 综上所述，已发表的数据和初步数据支持以下假设： 经酒精处理的动物的淋巴内容物破坏 PLAT 免疫和代谢稳态 通过 fTreg 扩展，拟议的研究将采用多种技术来检验该假设。 使用三个具体目标：(1) 来自酒精处理动物的淋巴将在初始 PLAT 中扩增 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 PLAT 失调，(3) 酒精引起的 PLAT 代谢失调与全身性相关 拟议研究的结果将提供对代谢后果的深入了解。 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 fTregs，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。 致力于培养全面发展的医师科学家，完成拟议的培训计划将 确保申请人准备好开始学术医学职业生涯。