This laboratory 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 preventive 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.
Key Projects Underway
The main projects in the laboratory currently seek to:
- Evaluate the clinicopathologic 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
- Clarify the relationship between NMMII regulation in fibroblasts, protomyofibroblasts, and myofibroblasts and tractional force generation
- In vitro techniques
- Animal models of wound contraction and skin graft contraction
- Investigation of human tissue