Regulation and modeling of transport across tissue barriers

项目摘要 液体、分子、蛋白质和细胞在全身的生理运输对体内平衡至关重要。 虽然细胞迁移和分子穿越细胞屏障等运输过程很好 已有文献记载，对穿越间质组织间隙和进入淋巴管的运输知之甚少。 淋巴管是维持组织内环境稳定和形成获得性免疫的关键 反应，因为它们是外周组织和淋巴结(LNS)之间的天然管道，其中 免疫反应是有形态的。由于微粒主要通过淋巴管穿梭，淋巴管 近年来，作为药物输送的潜在目标，特别是免疫药物，受到了相当大的关注 调制。通过间质组织的运输控制进入淋巴管的物质与进入血管的物质，从而 了解细胞外组织对于设计治疗方法至关重要。然而，我们还不完全了解如何 生理过程和条件，如间质流动或炎症，影响通过间质的运输 组织空间和淋巴管。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)淋巴运输及其调节，2)跨 细胞外组织？为了解决第一个问题，我们建议建立与生理相关的体外模型。 可以概括外周组织内情况的系统和都允许探测的纳米颗粒工具 具体的机制，包括液体流动和炎症，如何调节特定的淋巴运输。 这些研究的结果将为淋巴运输的调节、新的模型系统提供新的见解 用于研究淋巴传输，以及最大限度地针对治疗的淋巴传输的新设计标准 目的。为了解决第二个问题，我们将结合两种技术：多粒子跟踪(MPT)和 活体组织切片培养。MPT使用纳米颗粒随时间扩散来提取有关组织的信息 网格间距或微观流变学，为研究流动等生理过程提供了一种媒介。活组织 切片培养在体外维持组织结构，并允许对间质组织结构进行实时评估。 结合这些技术的结果将提供对生理过程的更好理解 影响细胞外空间，并为治疗药物跨越细胞外组织的设计标准提供见解 障碍。总之，拟议的工作将促进我们对生理过程的了解 淋巴运输及其调节，也揭示了炎症，间质流动， 和水肿会影响细胞外组织间隙。归根结底，我实验室研究的愿景是设计关键的 供更广泛的社区使用的科学方法，确定设计标准和计算 预测跨越生物屏障的传输和设计治疗方法及其传递的模型 利用淋巴管生理学治疗疾病的工具。

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.