Novel Mechanisms in the Resolution of Post-Surgical Lymphedema

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Project Summary This is a mentored clinical scientist research career development proposal for a junior physician who clinically treats post-surgical lymphedema and is training to become an independent investigator. 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 cancer (e.g, breast cancer and melanoma). 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. There is currently no cure for this disease. Management includes compression, excisional procedures, and microsurgical operations vascularized lymph node transfer and lymphovenous bypass (LVB). During LVB, lymphatics in the affected extremity are anastomosed to veins to bypass the injured area. The operation is technically challenging, time consuming, and requires advanced equipment. One-third of patients develop lymphedema following lymphadenectomy. The two thirds of those patients that do not develop lymphedema have transient postoperative limb swelling which resolves spontaneously. Similarly, a mouse tail model of lymphedema spontaneously resolves the swelling. We propose the novel hypothesis that lymphedema-induced spontaneous lymphovenous shunts and lymphangiogenesis lead to the physiological resolution of lymphedema. We use a murine tail model of lymphedema to test our hypothesis. In Aim 1, we will determine the mechanism responsible for spontaneous resolution of lymphedema. In addition, this proposal presents an innovative approach using tissue nanotransfection technology (TNT) to induce lymphovenous shunts and lymphangiogenesis to improve lymphedema. In Aim 2, we hypothesize that TNT can be used to topically, focally deliver genetic cargo to improve lymphedema by targeting the C-type lectin like receptor (CLEC- 2), Syk, and Slp76 pathways which keep lymphatics separated from veins. Inducing lymphovenous shunts would act similarly to LVB currently performed clinically to treat lymphedema. In summary, these experiments will be high impact in identifying the mechanism of spontaneous lymphatic resolution. The proposed work adopts a novel approach to managing lymphedema using focal, non-global TNT directly at the affected area. The candidate is an Assistant Professor at Indiana University who is dedicated to becoming a physician-scientist. He has obtained a previous Master’s degree in translational and clinical research at Harvard Medical School. The candidate has multiple pilot and foundation grants, a startup research package, dedicated laboratory space, and 40% protected time which will be increased to 75% upon obtaining the K08 grant. There is an expert mentorship panel, including the Vice-Chair of Surgery and the candidate’s Division Chief, who are well funded and experienced in mentoring physician scientists. There is strong institutional commitment which will facilitate the candidate transition to an independent investigator.