EXCEED THE SPACE PROVIDED. Tissue contraction is an integral part of wound closure; however, excessive or abnormal contraction of tissues can lead to pathological contractures, tissue deformation and loss of tissue function, all major health problems in the United States. The long-term goal of this project is to understand the cellular basis underlying wound contraction and tissue contracture by studying the formation and function of the myofibroblast. Myofibroblasts are specialized fibroblasts that express smooth muscle alpha-actin (SMAA) and assemble contractile structural elements as part of their ability to generate the contractile force responsible for tissue contraction. Our recent studies have demonstrated that the mechanical properties of the extracellular matrix are critical in regulating SMAA expression and myofibroblastformation and function. These results have led to a series of novel hypothesis regarding mechano-regulation of myofibroblast formation and function: (i) mechano-regulation of the SMAA promoter in myofibroblasts is mediated by changes in actin dynamics; (ii)myocardin-related transcription factor A (MRTF-A) couples mechano- regulated changes in actin dynamics with gene expression by translocating from cytoplasmic actin to the nucleus; (iii) MRTF-A activates a subset of SM-specific cytoskeletal proteins, in addition to SMAA, in myofibroblasts; (iv) MRTF-A activation of this subset of SM-specificcytoskeletalproteins is responsible for assembly of functional contractile structural elements and contractile force generation in myofibroblasts. We will test these hypotheses by use of various types of three-dimensional collagen lattices that we have demonstrated can provide different mechanical environments and mimic the process of wound contraction. It is our hope that an understanding of the mechanism of mechano-regulation of myofibroblast formation and function will provide future opportunities for targeting specific signaling pathways and transcriptional regulatory events to regulate wound healing and pathological contractures. PERFORMANCE SITE ========================================Section End===========================================
