ENHANCED TISSUE REGENERATION OF OROFACIAL MUSCLES

Emory University, Atlanta GA

Investigators

Linked publications & trials

Abstract

DESCRIPTION (Adapted from the Applicant's Abstract) Myoblast transplantation has potential benefits for both muscle replacement and in the enhancement of muscle regeneration. Genetically engineered myoblasts may serve to deliver growth and differentiation factors locally to skeletal muscle in patients with developmental defects, disease or trauma. Muscle regeneration follows an orderly progression of biologic events from activation of muscle precursor cells (satellite cells), to formation of multinucleated myofibers from the fusion of satellite cells and finally, to maturation of the myofibers. The regenerative response of muscle may be enhanced or retarded by factors that affect the activation, proliferation and/or fusion of satellite cells. The investigators have shown that masseter muscles of mice have an impaired regenerative ability in both disease and injury due in part to quantitative and qualitative deficiencies of the intrinsic myoblast populations within these muscles. The main objectives of this proposal are (1) to evaluate the ability of growth factors to increase the proliferative capability of masseter muscle stem cells in vitro and using this knowledge, to use genetically engineered muscle cells as a means of enhancing muscle repair; (2) to define the role of the transcription factor, NFAT (nuclear factor of activated T cells), in regulating gene expression during muscle repair and maintenance. NFAT is a transcription factor, originally identified in T cells that is also expressed by non-lymphoid cells including skeletal muscle. The role of NFAT isoforms in non-lymphoid cells is unknown. However, pharmacologic agents which block NFAT-mediated transcription in skeletal muscle cells affect muscle cell growth and differentiation, thereby suggesting a critical role for NFAT proteins in skeletal muscle. Manipulation of the signal transduction pathways involved in regulating NFAT-mediated transcription during muscle repair and maintenance could be a target for drug development. The specific hypotheses to be tested are (1) masseter myoblasts will grow normally with the proper supply of growth factors; (2) muscle regeneration can be enhanced using regulated expression of growth and differentiation factors via myoblast-mediated gene therapy; (3) changes in skeletal muscle physiology result in activation of NFAT-mediated transcription; (4) NFAT regulates the expression of proteins with known roles in muscle growth, repair and maintenance; and (5) alterations in muscle repair and maintenance occur when NFAT-mediated transcription in skeletal muscle is specifically blocked.