Quantifying the role of lymphatics in lipid metabolism and transport

描述（由申请人提供）： 微淋巴循环的研究是令人兴奋和富有挑战的，因为它在免疫细胞运输，癌症转移和脂质代谢中的重要性正在迅速得到越来越多的重视，并且它在这些过程中的积极生物学作用现在才被发现。由于这一系统的复杂性，非常需要开发新的定量工具和模型，并使用这些新工具以跨学科方式探索这些积极作用。该提案涉及脂质转运和代谢中的代谢物的积极作用，这是一个非常不了解的主题，并且存在很少的工具。该补助金的培训阶段将集中在两个具体目标，为淋巴/脂质相互作用的未来研究奠定基础：1）开发肠淋巴微环境的组织工程模型，重现脂质转运功能，2）确定纳米颗粒转运的相对动力学穿过肠微环境的组织工程结构。肠道微环境的组织工程模型将是一个有用的工具，阐明控制淋巴功能的生物学机制，以及提供反馈到新的口服给药方法的设计和开发。每个目标将在独立研究阶段继续进行，包括体内研究，以提供更完整，相关的图片，以了解代谢物如何积极调节脂质转运。这些体内研究将重点关注脂质在肠道中的作用，并提供关于脂质环境如何影响身体其他部位淋巴泵功能的整体图片。 相关性-尽管脂肪酸在肠道脂质转运中起着关键作用，但几乎不知道它是如何被积极调节的，也不知道脂肪酸对脂质转运和代谢的生物学作用。一些临床相关性和实验观察已经将两者联系起来，但这项拟议的研究将建立关于代谢物如何积极影响脂质代谢的基础研究，并将开发定量和相关的体内和体外工具，用于研究淋巴内皮细胞的脂质运输和加工，以及用药物递送系统靶向代谢物。这项工作将有助于最终设计合理的治疗方法来治疗水肿，肥胖和其他相关疾病。

DESCRIPTION (provided by applicant): Project Summary - Research in microlymphatic circulation is exciting and rich in challenges as its importance in immune cell trafficking, cancer metastasis, and lipid metabolism are quickly becoming more appreciated and as its active biological 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. The training stage of this grant will focus on two specific aims to lay the groundwork for future studies in lymphatic/lipid interactions: 1) to develop a tissue engineered model of the intestinal lymphatic microenvironment that recapitulates lipid transport functions and 2) to determine relative kinetics of nanoparticle transport across the tissue engineered construct of the intestinal microenvironment. The tissue engineered model of the intestinal microenvironment will be a useful tool for elucidating the biological mechanisms that control lymphatic function and as well as for providing feedback into the design and development of new oral drug delivery methods. Each of the aims will be continued during the independent research phase with the inclusion of in vivo studies to provide a more complete, relevant picture as to how lymphatics actively regulate lipid transport. These in vivo studies will focus on the role of lipids in the gut as well as provide a global picture as to how the lipid environment influences lymphatic pump function elsewhere in the body. Relevance - Despite the critical role of lymphatics in lipid transport in the intestine, almost nothing is known about how it is actively regulated or about the biology of lipid transport and metabolism by lymphatics. Some clinical correlations and experimental observations have linked the two, but this proposed research will establish foundational studies on how lymphatics actively affect lipid metabolism and will develop quantitative and relevant in vivo and in vitro tools for studying lipid trafficking and processing by the lymphatic endothelium as well as targeting lymphatics with drug delivery systems. This work will contribute to the eventual design of rational therapies to treat lymphedema, obesity, and other related disorders.