Regulation and modeling of transport across tissue barriers

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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.