Role of the GI lymphatic system in hormonal signaling and nutrient metabolism

胃肠道淋巴系统在激素信号传导和营养代谢中的作用

• 批准号: 9789261
• 负责人: Min Liu
• 金额: $ 59.39万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-20 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9789261
• 关键词: Address; Affect; Area; Blood Circulation; Chronic; Chylomicrons; Conscious; Corticosterone; Data; Dependence; Dextrins; Dietary Fats; Dose; Ensure; Enterocytes; Enteroendocrine Cell; Estrous Cycle; Female; Fistula; Food; Gastrointestinal tract structure; Glucocorticoids; Glucose; Health; Hepatic; Hormone secretion; Hormones; Impairment; Inflammation Mediators; Inflammatory disease of the intestine; Ingestion; Insulin; Intestines; Knowledge; Lamina Propria; Lipids; Liver; Lymph; Lymphatic; Lymphatic System; Macronutrients Nutrition; Mediating; Metabolic; Metabolic hormone; Modeling; Mucous Membrane; Muscle; Nutrient; Organ; Ovarian hormone; Peripheral; Physiological; Physiology; Plasma; Process; Proteins; Radiolabeled; Rattus; Regulation; Request for Applications; Research; Role; Sex Differences; Signal Transduction; Source; Specificity; Stomach; Testing; Tracer; Triglycerides; Vagus nerve structure; absorption; cell type; cholesterol absorption; energy balance; ghrelin; glucagon-like peptide 1; glucose tolerance; glucose uptake; hormonal signals; improved; in vivo; incretin hormone; insulin secretion; intestinal villi; lymph flow; lymphatic circulation; male; mast cell; novel; nutrient metabolism; prevent; response; sex; sex cycle

Project Summary While the physiological importance of lymph chylomicron transport is well-documented, the physiological roles of other lymph factors remain poorly understood. This is a critical area for additional new research, as indicated in the RFA, which requests that applications determine “how the signals lymphatics are receiving may affect their function and, thus overall intestinal function”. In order to study these relationships, we will use the rat lymph-fistula model, a novel and powerful paradigm that is routine in our lab, to study the secretion of hormones and other GI factors in vivo. Using this paradigm, we initially demonstrated that lymphatic concentrations of incretin hormones (GLP-1, GIP) are markedly higher than those in the portal or systemic circulation. Our new preliminary data indicate the intriguing possibility that the lymph also transports locally-produced glucocorticoid hormones in response to dietary lipids, and that the lymphatic transport of dietary lipids and hormones varies in a sex- and/or estrous cycle-dependent manner. The present proposal addresses the overall hypothesis that the transport and signaling of hormones and related factors within the GI lymphatic system is necessary for normal functioning of the GI tract and for overall metabolic health. Aim 1 determines the physiological relevance of high incretin concentrations in intestinal lymph. We assess the impact of lymph diversion on glucose absorption and distribution, and determine the mechanisms by which the stomach regulates incretin secretion during nutrient ingestion. Aim 2 determines the physiological relevance of nutrient-induced glucocorticoid hormones in intestinal lymph. We identify the source of the lymphatic glucocorticoid response to lipids, and determine the extent that lymphatic glucocorticoids regulate lipid absorption and its associated proinflammatory response. Aim 3 determines the role of sex and the estrous cycle in intestinal lymph physiology. We evaluate the extent that lymphatic transport functions (for chylomicrons, incretins, inflammatory mediators, and glucocorticoids) vary with sex and/or the estrous cycle, and test the mechanistic role of ovarian hormones in these processes. This multi-PI proposal leverages the complementary expertise of a highly collaborative team that includes Dr. Patrick Tso (expert in GI lymphatics and metabolic hormones), Dr. Yvonne Ulrich-Lai (expert in the HPA axis and corticosterone signaling), and Dr. Min Liu (expert in ovarian hormone signaling and energy balance).

项目摘要 虽然有据可查的淋巴胆小物传输的身体重要性，但 其他淋巴因子的生理作用仍然鲜为人知。这是一个新的新的领域 如RFA所示，研究要求应用程序确定“信号淋巴管的方式” 接收可能会影响其功能，从而影响整体肠功能”。为了研究这些关系，我们 将使用我们实验室中常规的新型且强大的范式使用大鼠淋巴 - 菲斯塔模型来研究 体内骑马和其他GI因子的分泌。使用此范式，我们最初证明了 增加激素（GLP-1，GIP）的淋巴浓度明显高于门户或 全身循环。我们的新初步数据表明淋巴也有可能运输的可能性 局部生产的糖皮质激素肌肉响应饮食脂质，以及淋巴运输的 饮食脂质和骑马以性别和/或发情循环依赖性方式变化。目前的提议 解决了总体假设，即gi中激素的传输和信号传递及相关因素 淋巴系统对于胃肠道的正常功能和整体代谢健康是必需的。目标1 确定肠道淋巴上高增加浓度的物理相关性。我们评估 淋巴转移对葡萄糖滥用和分布的影响，并确定该机制 胃会调节营养摄入期间增加的分泌。 AIM 2确定的身体相关性 营养诱导的肠道淋巴中的糖皮质激素。我们确定淋巴的来源 糖皮质激素对脂质的反应，并确定淋巴糖皮质激素调节脂质的程度 AIM 3决定了性和发情的作用 肠道淋巴生理中的循环。我们评估淋巴运输功能的程度（对于 乳糜微粒，肠降低，炎症介质和糖皮质激素随性别和/或发情周期变化 并测试卵巢龙骨在这些过程中的机械作用。该多PI提案利用了 一支高度协作团队的专业知识，包括帕特里克·TSO博士（GI淋巴管专家 和代谢激素），Yvonne Ulrich-Lai博士（HPA轴和皮质酮信号的专家）和Yvonne Ulrich-Lai博士（HPA轴和皮质酮信号的专家）和博士，以及博士。 Min Liu（卵巢马信号传导和能量平衡的专家）。