PROJECT SUMMARY Secondary lymphedema is a morbid condition affecting over 5 million patients in the United States. Patients with this condition develop lymphatic retention, which progresses to irreversible subcutaneous fibroadipose deposition in the affected extremity. As a result, patients experience chronic pain, decreased mobility and function, open wounds, and overall reduced quality-of-life. In Aim 1, I will examine how a stimulation of a signaling mediator which augments adipocyte differentiation may reduce overall fibroadipose deposition by preventing the proliferation of pathologic stem cell populations. In Aim 2, I will examine how inhibition of a pro-survival signaling mediator may impact adipocyte and pre-adipocyte survival. In the process, I seek to understand whether specific subsets of these cells are more likely to undergo apoptosis. Finally, in Aim 3, I seek to develop a local cell therapy which obviates the systemic adverse effects of therapies which modify cell differentiation or survival. In the process, I will have developed a therapy which is capable of secreting microRNA, paving the way for a new class of cell therapeutics. The career development award is indispensable for my maturation as a physician-scientist, to serve as a scientific and clinical leader performing research which is inspired by the challenges my patients face, rigorous in its evaluation of the underlying pathogenesis of this condition, and translational in its consideration of treatment strategies. I am supported by a team of mentors with expertise in stem cell and adipocyte biology, clinical lymphedema management, and in academic plastic surgery leadership. I am also supported by a team of additional scientific advisors with expertise in lymphedema biology, cell therapy, and translational medicine. The institution is committed to my success, with protected time for activities proposed in this award, laboratory space, salary support, and laboratory funding. During the 5-yea