Regulation and modeling of transport across tissue barriers

项目摘要 液体、分子、蛋白质和细胞在整个身体中的生理运输对于体内平衡是至关重要的。 虽然运输过程，如细胞迁移和分子通过细胞屏障， 尽管有文献记载，但对穿过间质组织间隙并进入淋巴管的转运知之甚少。 淋巴管对于维持组织稳态和形成适应性免疫至关重要 淋巴结（LN）是外周组织和淋巴结（LN）之间的天然管道， 免疫反应的形成。由于微粒主要通过淋巴管穿梭，因此， 近年来，作为药物递送的潜在靶点，特别是免疫递送的潜在靶点，受到相当大的关注。 调变跨间质组织的转运控制进入淋巴管与血管的物质， 了解细胞外组织对设计治疗方法至关重要。然而，我们还没有完全理解 生理过程和状况如间质流动或炎症影响跨间质的转运 组织间隙和组织间隙。我的研究计划将回答两个关键问题：1）如何 生理过程影响1）淋巴转运及其调节，和2）跨膜转运。 细胞外组织为了解决第一个问题，我们建议开发生理相关的体外模型 可以概括外周组织内条件的系统和纳米粒子工具， 具体机制，包括液体流动和炎症，如何具体调节淋巴转运。 这些研究的结果将为淋巴转运的调节提供新的见解， 用于研究淋巴转运，以及新的设计标准，以最大限度地靶向淋巴转运， 目的为了解决第二个问题，我们将结合联合收割机两种技术：多粒子跟踪（MPT）和 活的离体组织切片培养物。MPT使用纳米粒子随时间的扩散来提取组织信息 网格间距或微观流变学，并提供了一种研究生理过程，如流动的媒介。活组织 切片培养物保持离体组织结构并允许实时评估间质组织结构。 结合这些技术的结果将提供更好的理解生理过程如何 影响细胞外空间，并为治疗剂穿过细胞外组织的设计标准提供见解 隔栏.总之，所提出的工作将推进我们对生理过程的认识， 淋巴运输及其调节，也揭示了炎症，间质流动， 和水肿影响细胞外组织空间。最终，我实验室的研究目标是设计出 科学的方法被更广泛的社区使用，确定设计标准和计算 模型来预测跨生物屏障的运输，并设计治疗方法及其输送 通过利用淋巴管生理学来治疗疾病的载体。

Project Summary Physiological transport of fluid, molecules, proteins, and cells throughout the body is critical for homeostasis. While transport processes like cell migration and molecular passage across cellular barriers are well documented, less is known about transport across the interstitial tissue spaces and into lymphatic vessels. Lymphatic vessels are critical for maintenance of tissue homeostasis and forming the adaptive immune response, as they are the natural conduit between peripheral tissues and the lymph nodes (LNs), where the immune response is shaped. Because particulates are primarily shuttled via lymphatic vessels, lymphatics have received considerable attention in recent years as potential targets for drug delivery, particularly for immune modulation. Transport across interstitial tissue governs what enters lymphatic vessels vs. blood vessels and thus understanding extracellular tissues is vital to design therapeutics. However, we do not yet fully understand how physiological processes and conditions such as interstitial flow or inflammation affect transport across interstitial tissue spaces and into lymphatics. My research program will answer two key questions: 1) How do physiological processes affect 1) lymphatic transport and its regulation, and 2) transport across extracellular tissue? To address the first question, we propose to develop physiologically relevant in vitro model systems that can recapitulate conditions within peripheral tissues and nanoparticle tools that both allow probing how specific mechanisms, including fluid flow and inflammation, modulate lymphatic transport specifically. Results from these studies will provide new insights into regulation of lymphatic transport, new model systems for studying lymphatic transport, and new design criteria to maximize targeting lymphatic transport for therapeutic purposes. To address the second question, we will combine two techniques: multiple particle tracking (MPT) and live ex vivo tissue slice cultures. MPT uses nanoparticle diffusion over time to extract information about tissue mesh spacing or microrheology and provides a medium for studying physiological processes like flow. Live tissue slice cultures maintain tissue structure ex vivo and allow for real-time assessment of interstitial tissue structures. Results from combining these techniques will provide a better understanding of how physiological processes affect extracellular spaces and provide insights into design criteria for therapeutics to cross extracellular tissue barriers. In summary, the proposed work will advance our knowledge about physiological processes governing lymphatic transport and its regulation, and also shed light into how processes like inflammation, interstitial flow, and edema affect extracellular tissue spaces. Ultimately, the vision for my lab’s research is to design crucial scientific methods to be used by the broader community, identify design criteria and computational models to predict transport across biological barriers, and design therapeutics and their delivery vehicles for treating diseases by harnessing lymphatic vessel physiology.