Quantifying the role of lymphatics in lipid metabolism and transport

项目摘要-淋巴循环的研究是令人兴奋的，充满挑战，因为它的重要性 在免疫细胞运输、癌症转移和脂质代谢中， 而它在这些过程中的积极作用直到现在才被发现。因为这个问题的复杂性 因此，非常需要开发新的定量工具和模型，并使用这些工具和模型。 新的工具，以跨学科的方式探索这些积极的作用。该提案涉及积极作用 脂质转运和代谢中的代谢动力学，这是一个非常不了解的话题， 我们将通过三个具体目标来解决这些问题：1）识别和量化 关键受体和蛋白质在脂质跨淋巴管内皮细胞转胞吞中的作用 使用我们以前开发的组织工程模型的乳房; 2）开发和表征一种在乳房中的组织工程模型。 肠系膜淋巴管对脂质的淋巴摄取的体内模型，并使用该模型来评估 淋巴功能全面受损（在基因敲除小鼠中）对脂质吸收的影响; 3） 确定高脂血症对淋巴功能的影响（特别是内在的功能）， 淋巴泵），使用体外、体内和分离的血管模型的组合。总的来说，这三个 aims将研究脂质和淋巴功能的平衡，并提供新的见解， 淋巴或脂质功能障碍对脂质稳态和组织液平衡的后果。

Project Summary - Research in the lymphatic circulation is exciting and rich in challenges as its importance in immune cell trafficl<ing, cancer metastasis, and lipid metabolism are quicl<ly becoming more appreciated and as its active roles in such processes are only now being discovered. Because of the complexity of this system, there is great need for new and quantitative tools and models to be developed, and to use those new tools to explore these active roles in interdisciplinary manners. This proposal addresses the active role of lymphatics in lipid transport and metabolism, a topic which is very poorly understood and for which very few tools exist to study It. We will address these issues through three specific aims: 1) Identify and quantify the role of key receptors and proteins involved in the transcytosis of lipid across lymphatic endothelial cells using our previously developed tissue engineered model of the lacteal; 2) develop and characterize an in vivo model of lymphatic uptake of lipid by mesenteric lymphatics and use this model to assess the consequences of globally impaired lymphatic function (in knock-out mice) on lipid uptake by lymphatics; 3) determine the effects of hyperiipidemia on lymphatic function (particularly the function of the intrinsic lymphatic pump) using a combination of in vitro, in vivo, and isolated vessel models. Collectively these three aims will investigate the balance of lipid and lymphatic function and provide new insight into the resulting consequences of lymphatic or lipid dysfunction on lipid homeostasis and tissue fluid balance.