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

项目摘要 虽然淋巴乳糜粒运输的生理重要性已经得到了很好的证明，但 其他淋巴因子的生理作用仍然知之甚少。这是其他新产品的关键领域 研究，如RFA中所指出的，它要求应用程序确定“淋巴管信号如何 接受治疗可能会影响其功能，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，一个新的和强大的范例，在我们的实验室，以研究 体内激素和其他胃肠道因子的分泌。使用这个范例，我们最初演示了 淋巴中的生长素激素(GLP-1、GIP)浓度明显高于门脉或门静脉。 体循环。我们新的初步数据表明，淋巴也有可能运输 局部产生的糖皮质激素对饮食脂质的反应，以及淋巴运输 饮食中的脂类和荷尔蒙随着性别和/或发情周期的不同而变化。目前的建议 解决了激素和相关因子在胃肠道内的运输和信号传递的总体假设 淋巴系统对于胃肠道的正常功能和整体新陈代谢健康是必不可少的。目标1 确定肠淋巴中高浓度的胰岛素的生理学相关性。我们评估 淋巴分流对葡萄糖吸收和分布的影响，并确定其机制 在营养摄入过程中，胃调节胰岛素的分泌。目标2确定了生理相关性 肠淋巴中营养诱导的糖皮质激素。我们找出淋巴的来源 糖皮质激素对脂质的反应，并确定淋巴糖皮质激素调节血脂的程度 吸收及其相关的促炎反应。目标3确定性别和发情期的作用 肠道淋巴生理循环。我们评估淋巴运输功能的程度(对于 乳糜粒、胰岛素、炎症介质和糖皮质激素)随性别和/或发情周期的不同而变化， 并测试卵巢激素在这些过程中的机械作用。此多PI方案利用 高度协作的团队的互补专业知识，其中包括Patrick Tso博士(GI淋巴学专家 和代谢激素)，Yvonne Ulrich-Lai博士(HPA轴和皮质酮信号方面的专家)和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).