Grants Funded

Abstract

Project Summary: Radiation therapy is a fundamental modality in the comprehensive treatment of cancer with half of all cancer patients receiving radiation during their course of illness. While radiation is highly effective in stimulating local tumor cell death, the negative side effects of ionizing radiation on the surrounding "normal" tissue remain a limiting factor. Acute skin injury following ionizing radiation is typically self-limiting. However, late radiation induced skin changes lead to progressive and irreversible fibrosis characterized by disorganized collagen deposition resulting in impaired wound healing and regenerative plasticity. Despite major advances in the precision and fidelity with which radiation therapy has been administered over the past decades, therapies to mitigate its negative side effects on surrounding healthy tissue are lagging behind. Macrophages have been shown to play an important role, although the mechanisms underlying this process remain poorly understood. We have assessed the interaction of fibroblasts and macrophages following radiation using a biomimetic co-culture system. Our preliminary data indicate that exposure to radiation leads to transcriptional and functional changes in macrophages that result in a pro-fibrotic phenotype. In this proposal, we aim to deepen our understanding of the mechanisms underlying macrophage driven fibrosis. We will determine how radiation affects macrophage polarization and function in vitro. In addition, we will therapeutically target macrophages using Rosiglitazone to mitigate fibrosis in an in vivo hindlimb radiation model.

Impact Statement: Treatment strategies that are directed towards preventing fibrosis prior to its manifestation will be critical in successfully addressing radiation induced fibrosis. The data derived from this study will allow us to elucidate the mechanisms of how radiation drives fibrosis through interaction of macrophages/fibroblasts. Furthermore, we will utilize Rosiglitazone, FDA approved diabetes drug, to mitigate the development and progression of fibrosis. If successful, the findings from this proposal will lead into clinical trials to prophylactically treat patients undergoing radiation therapy.

Biography
While I was born in St. Petersburg, Russia, my family relocated to Germany where I spent the formative years of my professional education. After developing a keen interest in plastic surgery I decided to pursue a career as an academic surgeon. After graduating from medical school, I was privileged to complete a postdoctoral fellowship under the mentorship of Drs. Gurtner and Longaker at Stanford University where I focused on projects in the fields of regenerative medicine, wound healing and tissue engineering. Through their mentorship I acquired a skill set to independently pursue complex scientific projects. I thereafter completed residency training and microsurgery fellowship at the University of Michigan that allowed me to establish a practice caring for primarily cancer patients. During that time I have remained strongly invested in research and have completed research under Dr. Levi's mentorship and was fortunate to receive funding through the PSF. I have joined the Department of Plastic and Reconstructive Surgery at The Ohio State University as Assistant Professor, where I have established a laboratory focused on identifying pathways to mitigate radiation induced soft tissue fibrosis. I believe that support provided through the PSF would form an integral part in building my academic career.