Regeneration of lymphatic valve after injury

University Of Nebraska Lincoln, Lincoln NE

Investigators

Linked publications, trials & patents

Abstract

Secondary lymphatic valves play a crucial role in maintaining unidirectional lymph flow and preventing backflow during lymphatic transport. These delicate bi-leaflet structures are frequently damaged during surgical interventions, particularly cancer-related lymph node dissections, leading to lymphatic dysfunction and secondary lymphedema—a chronic, incurable condition affecting millions in the United States. Despite its prevalence, no FDA-approved drug is available to treat lymphedema, and the mechanisms underlying valve regeneration remain largely unknown. The long-term goal of this project is to advance the mechanistic understanding of lymphatic valve regeneration after injury. The overall objective is to determine the extent to which lymphatic valves regenerate when lymphatic flow is disrupted and to define the flow-responsive signaling pathways that orchestrate this regenerative process. Our central hypothesis is that lymphatic valves regenerate at sites of sprouting in response to injury-induced alterations in lymphatic flow, and that mechanosensitive pathways activated by oscillatory shear stress are essential to this response. To test the central hypothesis, we propose two specific aims: 1) Define the cellular dynamics of lymphatic valve regeneration following injury. 2) Elucidate the mechanotransductive pathways activated by lymph flow during valve repair and regeneration. To achieve these aims, we will use innovative animal models of lymphatic injury, high-resolution intravital imaging through chronic windows, and microfluidic labon- a-chip platforms that mimic physiological flow conditions. By combining in vivo and in vitro methods, we will track valve regeneration in real time and pinpoint essential regulators of flow-mediated repair. This project is innovative in its use of longitudinal imaging, fluidic modeling, and injury models to dissect lymphatic regeneration with high spatial and temporal resolution. The significance of this work lies in its potential to uncover fundamental mechanisms of lymphatic valve regeneration and lay the groundwork for future therapeutic strategies to restore valve function and prevent lymphedema.