Regulation and modeling of transport across tissue barriers

跨组织屏障运输的调控和建模

• 批准号: 10434155
• 负责人: Katharina Maisel
• 金额: $ 36.6万
• 依托单位: UNIV OF MARYLAND, COLLEGE PARK
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10434155
• 关键词: Address; Affect; Attention; Biological; Biological Models; Blood Vessels; Cells; Communities; Computer Models; Diffusion; Disease; Drug Delivery Systems; Drug Targeting; Edema; Engineering; Extracellular Space; Homeostasis; Immune response; Inflammation; Knowledge; Light; Liquid substance; Lymphatic; Lymphoid Tissue; Maintenance; Methods; Modeling; Molecular; Mucous Membrane; Particulate; Peripheral; Physiological; Physiological Processes; Physiology; Process; Proteins; Regulation; Research; Slice; Structure; Techniques; Therapeutic; Time; Tissues; Transport Process; Vision; Work; adaptive immune response; cell motility; delivery vehicle; design; draining lymph node; extracellular; fluid flow; immunoregulation; in vitro Model; insight; interstitial; lymph nodes; lymphatic circulation; lymphatic vessel; model design; nanoparticle; particle; programs; tool

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.

项目概要 液体、分子、蛋白质和细胞在全身的生理运输对于体内平衡至关重要。 虽然细胞迁移和分子穿过细胞屏障等运输过程很顺利 据文献记载，人们对穿过间质组织空间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 反应，因为它们是周围组织和淋巴结 (LN) 之间的天然管道，其中 免疫反应已形成。由于颗粒物主要通过淋巴管穿梭，因此淋巴管 近年来作为药物输送的潜在靶点受到了相当多的关注，特别是免疫药物输送 调制。跨间质组织的运输控制着进入淋巴管和血管的物质，因此 了解细胞外组织对于设计治疗方法至关重要。然而，我们还没有完全理解如何 生理过程和条件（例如间质流动或炎症）影响跨间质的运输 组织间隙并进入淋巴管。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，以及 2) 跨界运输 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 可以重现周围组织内条件的系统和都可以进行探测的纳米颗粒工具 包括液体流动和炎症在内的特定机制如何特异性调节淋巴运输。 这些研究的结果将为淋巴运输的调节、新模型系统提供新的见解 用于研究淋巴运输，以及最大限度地靶向淋巴运输以进行治疗的新设计标准 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有关组织的信息 网格间距或微流变学，并为研究流动等生理过程提供了媒介。活组织 切片培养物维持离体组织结构，并允许实时评估间质组织结构。 结合这些技术的结果将有助于更好地理解生理过程 影响细胞外空间并为穿越细胞外组织的治疗设计标准提供见解 障碍。总之，拟议的工作将增进我们对控制生理过程的了解 淋巴运输及其调节，也揭示了炎症、间质流动等过程如何 水肿影响细胞外组织间隙。最终，我实验室研究的愿景是设计关键的 更广泛的社区使用的科学方法，确定设计标准和计算 预测跨生物屏障的运输并设计治疗方法及其递送的模型 通过利用淋巴管生理学来治疗疾病的载体。