Fibrosis is a pathological wound healing response to chronic injurious stimuli that results in excessive extracellular matrix deposition and scarring. Almost every internal organ is vulnerable to fibrosis, which causes progressive deterioration in organ function and eventual failure. The human vocal folds are laryngeal connective tissues that develop unique structure/composition to withstand high frequency vibration (>100 Hz) during vocalization and repair minor injury without fibrotic scarring. Fibroblasts subjected to physiologically relevant vibration using an in vitro bioreactor exhibit a pattern of gene expression consistent with the composition of the superficial layer of the lamina propria (SLLP), the major vibratory layer of the vocal folds. This response includes significant increases in the expression of extracellular matrix molecules with antiscarring activity, including hyaluronic acid, decorin, and fibromodulin. The central hypothesis is that vibratory mechanical stimulation and the molecular mechanisms it activates promote an antifibrotic fibroblast phenotype. The long-term goal is to identify the molecular and biochemical mechanisms of vibratory mechanotransduction to rationally develop drugs for their therapeutic activation. This project's objective is to characterize the antifibrotic effects of vibration on fibroblast extracellular matrix metabolism and cytokine signaling and identify transcription factors that are probable upstream regulators of the antifibrotic phenotype.
The specific aims are to 1) characterize the effect of variation if vibratory frequency, amplitude, and duration on fibroblast matrix metabolism, 2) identify molecular mechanisms activated by vibratory stimulation that inhibit transforming growth factor beta signaling activity, and 3) identify probable transcriptional regulators of fibroblast response to vibratory stimulation. Analysis of vibratory mechanotransduction in the vocal fold SLLP is an innovative approach to gaining new insights into fibroblast matrix regulation that may lead to the development of novel therapies for fibrotic disease. Identification of candidate transcriptional regulators of the vibratory response will lead to therapeutic strategies that target either the transcription factors or signal transduction pathways implicated in their activity to inhibit/reverse the fibrotic response in multiple tissues and organs. Fibrotic disease is a major cause of organ failure and mortality. Currently there are few effective therapeutic options. The long-term goal of this project is to develop therapeutic agents for early intervention to inhibit/reverse fibrosis.
Fibrotic disease is a major cause of organ failure and mortality. Currently there are few effective therapeutic options. The long-term goal of this project is to develop therapeutic agents for early intervention to inhibit/reverse fibrosis.
| Kutty, Jaishankar K; Webb, Ken (2010) Vibration stimulates vocal mucosa-like matrix expression by hydrogel-encapsulated fibroblasts. J Tissue Eng Regen Med 4:62-72 |
