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

项目摘要 虽然淋巴乳糜微粒转运的生理重要性已被充分证明， 其他淋巴因子的生理作用仍然知之甚少。这是一个关键领域， 研究，如RFA中所示，要求应用程序确定“信号的物理特性如何 接受可能会影响他们的功能，从而影响整体肠道功能”。为了研究这些关系，我们 将使用大鼠淋巴瘘模型，这是我们实验室常规的一种新颖而强大的范式，来研究 体内激素和其他GI因子的分泌。使用这个范例，我们最初证明， 肠促胰岛素激素（GLP-1，GIP）的淋巴浓度明显高于门静脉或 体循环我们新的初步数据表明淋巴液也可以运输 局部产生的糖皮质激素对饮食脂质的反应，以及淋巴运输的糖皮质激素， 饮食脂质和激素以性别和/或发情周期依赖的方式变化。现时的建议 解决了总体假设，即激素和相关因素在胃肠道内的运输和信号传导 淋巴系统是胃肠道正常运作和整体代谢健康所必需的。要求1 确定肠淋巴液中高肠促胰岛素浓度的生理相关性。我们评估 淋巴转移对葡萄糖吸收和分布的影响，并确定淋巴转移的机制。 胃在营养摄取期间调节肠促胰岛素分泌。目标2确定了 肠淋巴液中营养诱导的糖皮质激素。我们确定淋巴管的来源 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 吸收及其相关的促炎反应。目的3确定性和发情的作用 肠淋巴生理学周期。我们评估淋巴转运功能的程度（对于 乳糜微粒、肠促胰岛素、炎症介质和糖皮质激素）随性别和/或发情周期而变化， 并测试卵巢激素在这些过程中的机制作用。此多PI提案利用了 包括帕特里克左博士（GI消化道专家）在内的高度协作团队的互补专业知识 Yvonne Ulrich-Lai博士（HPA轴和皮质酮信号传导方面的专家），以及Dr. 刘敏（卵巢激素信号和能量平衡专家）。

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).