Decoding the repair and immunomodulatory functions of lymphatic vessels in wound healing

PROJECT SUMMARY Proper skin restoration after the damage is vital for organismal survival. The lymphatic vascular system is spread throughout the human body and has a critical function in mammalian physiology. In physiological conditions, its main function is the regulation of tissue drainage, immunosurveillance, and regeneration. Lymphatic dysfunction causes lymphedema a medical condition that manifests as tissue swelling and fibrosis. This serious condition results in profound severe delays in wound repair and the formation of chronic non-healing wounds. The mechanism by which lymphatic vessels regulate skin repair is unexplored. Additionally, while the role of lymphatic vessels in immune cell egress from tissues is well-established, how lymphatic vessels may directly modulate immune function in damaged tissues is poorly-defined. Recently, I discovered that lymphatic vessels are actively remodeled during wound healing to form small capillaries which are present in close localization to the wound front and hair follicles. This remodeling is critical for optimal repair as skin-specific loss of lymphatic vessels results in a significant delay in wound closure accompanied by a massive infiltration of immune cells. This proposal aims to leverage these observations by 1) delineating the mechanisms and consequences of lymphatic vessel remodeling during skin repair, and 2) determining the role of lymphatic vessels and fluid pressure in macrophage behavior during skin repair. This research stands to have a significant clinical impact because it can serve as a basis for developing new therapeutic avenues for lymphedema ulcers and chronic wound management. In addition, career-oriented guidance from my mentor and advisors, along with career development activated during the K99 phase that includes formal coursework on grant writing and project management, will further facilitate my transition to the R00 phase and my long-term productivity as an independent academic investigator. Collectively, the proposed research and career development plans are expected to generate data with a significant impact on understanding the repair and immunomodulatory functions of lymphatic vessels in skin repair and setting the basis of my future research as an independent researcher.