Assistant Professor

Division of Plastic and Reconstructive Surgery

DUMC 3974

Durham, NC 27710

919-684-8661 (phone)

919-684-5928 (fax)
howard.levinson@duke.edu           

         

 

 

Fibrosis and Wound Healing research in the Frank Hawkins Kenan Plastic Surgery Laboratories investigates the mechanisms of fibrosis and tissue remodeling and aims to develop a novel small molecule inhibitor to prevent fibrocontractile disease progression.

 

Approximately 80 million people worldwide are adversely affected by scar contracture; yet, current treatments are largely unsuccessful and preventative agents do not exist. There is a large unmet need for an effective pharmaceutical to prevent fibrosis. Fibrocontractile disease is ubiquitous throughout the human body. Scar contracture is putatively caused by fibroblast and myofibroblast contractility during the remodeling phase of repair.

 

Current hypotheses suggest that tractional force generation within these cells and subsequent scar contracture formation is primarily caused by myosin II activation and ensuing actin stress fiber formation, focal adhesion development, and cytoskeletal (microtubules and intermediate filaments) reorganization. However, it is unclear which myosins are activated in fibroblasts and myofibroblasts and how these myosins are regulated to increase tractional force generation and promote tissue remodeling. Filling this void is essential to the fulfillment of the long-term goal of developing a drug through small molecule high throughput screening, to prevent fibrocontractile disease. The current hypothesis is that as fibroblasts become activated and transition into protomyofibroblasts and myofibroblasts, Non muscle myosin II (NMMII) activation increases, either through upregulation of protein expression, through phosphorylation and activation of myosin regulatory light chain (MRLC), or through phosphorylation and inactivation of myosin phosphatase (MPYT), to enhance cellular tractional force generation and promote matrix remodeling.

 

The main project in the laboratory currently seeks to 1) evaluate the clincopathologic correlation between expression of NMMII (isoforms IIA, IIB, IIC), myosin light chain kinase (MLCK), Rho kinase, MRLC, MYPT, and a-SMA, as they relate to scar contracture progression; and 2) clarify the relationship between NMMII regulation in fibroblasts, protomyofibroblasts, and myofibroblasts and tractional force generation. Approaches include in vitro techniques, animal models of wound contraction and skin graft contraction, and investigation of human tissue.