ERI: Investigating How Tissue Stiffness and Fluid Flow Coordinate to Regulate Lymphatic Capillary Growth and Function

该奖项的全部或部分资金来自《2021年美国救援计划法案》(公法117-2)。该工程研究启蒙(ERI)奖将促进淋巴管的基础知识。这一结果将对未来解决淋巴疾病的战略产生积极影响。淋巴管从组织中排出液体，并将免疫细胞输送到全身。当血管受损时，后果包括组织内液体堆积，免疫功能减弱，和/或疾病进展。有效的治疗方法有限。这在一定程度上是因为人们还不完全了解这些血管对周围组织变化的反应。关于流体流动如何影响血管的生长和功能，人们已经知道了大量的信息。然而，人们对组织僵硬如何发挥作用知之甚少。这是令人惊讶的，因为僵硬的变化会发生在许多疾病中。这项工作将研究液体流动和组织硬度对血管生长和功能的联合影响。实验模型将被用来研究可变硬度和受控流体流动，以及它们的组合，以揭示淋巴管行为是如何被调节的。这项工作的结果将提高在研究淋巴疾病和制定治疗策略方面做出明智决定的能力。该项目方法结合了工程学和生物学的多个方面。它将为高级培训和跨学科的劳动力发展提供机会。研究、培训和指导还将扩大未被充分代表的群体参与研究的范围，并通过社区和教育外展吸引更多的人。尽管对淋巴管和流体诱导的生物力学力进行了广泛的研究，但淋巴机械生物学与组织僵硬的关系尚不清楚。关于组织中的细胞外基质硬度是如何影响淋巴管调节的，目前还存在总体上的知识空白。这一差距是显著的，因为基质重塑和进行性组织硬化对正常和疾病过程至关重要，而且许多淋巴疾病缺乏根治性治疗。其目的是将微流控芯片与响应性生物材料相结合，系统地将流体流动、压力和渐进性细胞外基质硬化应用于淋巴管内皮细胞。该项目将使用渐进式基质硬化来确定改变组织硬度在调节淋巴管中的机械传感器中的作用。然后，研究小组将应用机械输入的组合--流体流量、压力和刚度--将它们与特定的机械传感目标和功能结果相联系。结果将确定由协调的机械输入调节的机械感觉复合体，并扩大关于是什么驱动淋巴管调节和调节失调的视角。所获得的知识将推进淋巴机械生物学这一未被充分研究的领域，并提高就如何研究和治疗淋巴疾病做出明智决定的能力。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

This award is funded in whole or in part under the American Rescue Plan Act of 2021 (Public Law 117-2).This Engineering Research Initiation (ERI) award will advance fundamental knowledge about lymphatic vessels. The results will positively impact future strategies for addressing lymphatic disorders. Lymphatic vessels drain fluid from tissues and transport immune cells throughout the body. When vessels are compromised, consequences include fluid buildup in tissues, weakened immune function, and/or disease progression. There are limited effective treatments. This is in part because the response of these vessels to changes in the surrounding tissues is incompletely understood. Plenty of information is known about how fluid flow affects vessel growth and function. However, less is known about how tissue stiffness plays a role. This is surprising because changes in stiffness occur in many disorders. This work will study the combined effects of fluid flow and tissue stiffness on vessel growth and function. Experimental models will be used to study variable stiffness and controlled fluid flow, and their combination, to reveal how lymphatic vessel behavior is regulated. Results from this work will enhance the ability to make informed decisions about studying lymphatic disorders and developing treatment strategies. The project approach combines multiple aspects of engineering and biology. It will provide opportunities for advanced training and workforce development across disciplines. Research training and mentorship will also broaden participation of underrepresented groups in research and engage an even broader population through community and educational outreach.Despite extensive research on lymphatics and fluid-induced biomechanical forces, lymphatic mechanobiology as it relates to tissue stiffness is not well understood. There is an overall gap in knowledge around how extracellular matrix stiffness in tissues factors into lymph vessel regulation. This gap is significant since matrix remodeling and progressive tissue stiffening are critical to normal and disease processes, and many lymphatic disorders lack curative treatments. The objective is to combine a microfluidic chip with a responsive biomaterial to systematically apply fluid flow, pressure, and progressive extracellular matrix stiffening to lymphatic endothelial cells. The project will use progressive matrix stiffening to establish a role for changing tissue stiffness in regulating mechanosensors in lymph capillaries. The research team will then apply a combination of mechanical inputs—fluid flow, pressure, and stiffness—to link their interactions with specific mechanosensing targets and functional outcomes. Results will identify mechanosensory complexes that are regulated by coordinated mechanical inputs and expand perspectives on what drives lymph capillary regulation and dysregulation. The knowledge gained will advance an understudied area of lymphatic mechanobiology and enhance the ability to make informed decisions about how lymphatic disorders are studied and treated.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.