Grants Funded

Abstract

Project Summary: Lymphedema results from lymphatic dysfunction and is characterized by limb enlargement. It is most commonly caused by iatrogenic injury to the lymphatic system secondary to lymph node excision during the surgical management of breast cancer. It is estimated that 5-10 million Americans have lymphedema and 250 million people are affected worldwide. Morbidity from this chronic condition includes frequent infection, pain, and altered function. Current management has variable efficacy and there is no cure for this disease. Progression of lymphedema occurs with an inflammatory cascade resulting in fibrosis that is difficult to reverse. Clinically, prevention of lymphedema has gained traction with procedures such as immediate lymphatic reconstruction to connect disrupted afferent lymphatics at the time of axillary lymph node dissection to prophylactic decrease the risk of lymphedema. The “vascular delay phenomenon” is a well-described concept of flap physiology with many clinical applications used to increase flap viability. The approach employs a staged surgical procedure with selective partial disruption of the flap's blood supply to increase the robustness of the remaining vessels, followed by interval flap transfer 7-10 days later. Although vascular delay has been thoroughly studied, no investigation has been performed to determine if a similar “delay phenomenon” exists for lymphatic vessels. The investigators propose a novel concept of lymphatic preconditioning with staged disruption of lymphatics to protect against lymphatic dysfunction. This study uses a murine tail lymphedema model, which is well-established and has been optimized in our laboratory. In Aim 1, the effect of staged disruption of lymphatic vessels in the mouse tail 7 days apart will be compared to standard control murine lymphedema models with lymphatic disruption performed during the same surgery. The functional outcome will be determined with near-infrared lymphangiography and live-animal intravital micrsocopy. Lymphangiogenesis will be characterized with immunohistochemistry. In Aim 2, the transcriptome profile in the lymphatic preconditioned murine tail will be compared to the controls to determine molecular mechanistic changes that result from partial lymphatic disruption. This study has high translational clinical impact. It has the implications to change the paradigm of procedures known to cause lymphedema such as axillary lymphadenectomy.

Impact Statement: Lymphedema results from lymphatic dysfunction and is characterized by limb enlargement. It occurs in 30% of patients that have axillary lymph node excision in the treatment of breast cancer. It is estimated that 5-10 million Americans have lymphedema. Morbidity from this chronic condition includes frequent infection, pain, and altered function. There is currently no cure for this disease. The vascular delay phenomenon is a well-described concept with many clinical applications used to increase flap viability with staged partial disruption of the blood supply. The investigators propose a novel concept of “lymphatic delay” with staged disruption of lymphatics for protection against lymphatic dysfunction. This study has high translational clinical impact.

Biography
I started medicine with the fundamental goal of alleviating patient suffering and improving their quality of life. I was shaped by my academic mentors as I progressed through my general surgery residency (University of California San Diego), 2-year research fellowship and Master’s degree in translation/clinical research (Harvard Medical School), plastic surgery fellowship (Harvard), and microsurgery fellowship (Johns Hopkins). My mentors allowed me to realize that academic medicine facilitates a profound effect on patients with direct management, teaching others that will care for patients, and research to guide innovation in the field to optimize therapy. I started my academic practice at the Indiana University School of Medicine. I started a laboratory focused on lymphedema. I obtained pilot grant funding from the Plastic Surgery Foundation (PSF) to develop a tissue nanotransfection technology (TNT) application for lymphedema and won the Academic Scholarship from the American Association of Plastic Surgeons (AAPS) in 2021. I won a Department of Defense Congressionally Directed Medical Research Program grant in 2021. I was subsequently awarded a K08 by the NIH NHLBI and an R21 by the NIH NIAMS for studying targeted gene therapy for lymphedema with tissue nanotransfection technology. This current proposal investigates a novel concept of lymphatic preconditioning to prevent lymphedema. The study has high translational impact.