Modifying adipocyte and pre-adipocyte cell fate in fibroadipose tissue of secondary lymphedema

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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-year career development award, I will build on my previous expertise with monitoring stem cell fate using lineage-tracing mouse models, and add new scientific expertise to my armamentarium with single-cell RNA sequencing and bioinformatics analysis. I will engage in workshops and seminars to build on my technical skillset, and develop essential laboratory leadership skills. Upon completion of my 4th year of the career development award, I will submit for my first R01 submission, with the goal of further advancing findings obtained during my career development award. Upon completion of the 5-year award period, I will expect to have established my scientific expertise in adipocyte biology, cell therapy, and lymphedema, and established my technical expertise in lineage-tracing and RNA sequencing, to contribute broadly to the scientific environment in my institution.