Grants Funded

Abstract
Dupuytren's disease is a fibrocontractile disease that can be severely debilitating. Diseased fascia contains nodules and cords, and although it is unknown why these structures develop, it has been proposed that nodules are the primary epicenter of disease progression. While some investigators believe that myofibroblasts are putatively responsible for causing Dupuytren's disease progression, it is interesting to note that not all nodules contain myofibroblasts. Then what causes Dupuytren's disease? All nodules contain fibroblasts that, like myofibroblasts, are rich in actin and myosin contractile proteins. Thus, it is proposed that fibroblasts and myofibroblasts within nodules cause Dupuytren's disease and it is the putative interaction between actin and myosin II within these cells that causes palmar fascia contractures. There are several well-characterized myosin II isoforms and upstream intracellular contractile signaling mediators that lead to activation of actin-myosin to cause cellular contractility. However, it is not known which signaling pathway predominates in Dupuytren's fibroblasts and which predominates in myofibroblasts. The long term goal of this work is to identify the contractile proteins that are active in Dupuytren's disease to allow for development of novel small molecule inhibitors to prevent disease progression. It is hypothesized that nodule fibroblasts are rich in MLCK and SMMHC, and nodule myofibroblasts are rich in ROCK1, MYPT1, and NMMHC. Both fibroblasts and myofibroblasts contain MRLC. The first specific aim studies protein expression in Dupuytren tissue by immunostaining human tissue and the second specific aim investigates the functional role of contractile proteins in myofibroblast rich and myofibroblast poor Dupuytren tissue by applying contractile agonists and protein antagonists to Dupuytren tissue strips attached to a tensiometer in a tissue culture bath.

Biography
Howard Levinson, MD, FACS is a double board certified General Surgeon and Plastic and Reconstructive Surgeon at Duke University Medical Center (DUMC). He is an Associate Professor in the Departments of Surgery and Pathology. Dr Levinson is the Director of Plastic Surgery Research and is the Principal Investigator of the Wound Healing and Fibrosis Laboratory at DUMC. Dr Levinson has an active clinical practice. He cares for patients both at DUMC and the Veterans Administration Hospital in Durham, North Carolina. Dr Levinson performs clinical research and leads a translational research team which is rooted in the basic science laboratory. He holds several translational patents. His team uses contemporary in vitro and in vivo disease models to understand the mechanisms of skin wound healing and scarring in both rodents and swine. His laboratory is funded by intramural as well as extramural grants. His funding portfolio includes past and present grants from industry sponsored research, foundation and society funding, and grants from the National Institutes of Health and Howard Hughes Medical Institute. Dr Levinson is also a national recognized key opinion leader in the field of skin regeneration as is evidenced by his consulting for GlaxoSmithKline, Johnson and Johnson, Heraeus Pharmaceuticals, Exoxemis, Allergan. He serves on the Wound Care Advisory board for Cardinal Health. He had served on multiple study sections for Department of Defense and the Plastic Surgery Foundation and has multiple collaborations with investigators both within and outside of DUMC. He has served as an ad-hoc reviewer for several scientific journals including The New England Journal of Medicine, Annals of Surgery, The American Journal of Physiology: Cell Physiology, e-PLOS, Journal of Surgical Research, Plastic and Reconstructive Surgery, and Molecular and Cellular Biochemistry.