investigator's application): Smooth muscle cells have been the subject of intense study because abnormal growth and proliferation of vascular smooth muscle cells is involved in the pathogenesis of atherosclerosis and hypertension. In particular, the various proximal signals that influence growth and differentiation of SM-cells including growth factors and their receptors and the intracellular signaling pathways have been extensively investigated. However, the cellular and molecular basis of smooth muscle differentiation is poorly understood. With this standpoint a central question in vascular biology relates to understanding the transcriptional control mechanisms underlying smooth muscle differentiation and diversity. The Study of this subject has been impeded by the lack of smooth muscle cell differentiation. The investigators have recently isolated and characterized the smooth muscle myosin heavy chain (SMHC) gene promoter. They further demonstrated that SM-myosin is expressed exclusively in SM-cells and the SMHC gene promoter is transcribed only in the smooth muscle cells but not in other cell types. These results led us to hypothesize that the SMHC gene promoter contains cis-DNA elements which restrict its expression to SM-cells by interacting with a set of SM-cell specific trans-factors. Therefore, the primary goal of this project is to determine the factors which restrict SMHC gene expression to SM-cells using in vitro and in vivo gene transfer methodology. A second important goal is to identify the early steps in SM-cell differentiation using the SM-cell specific markers and the SMHC-gene linked to a LacZ reporter in transgenic mice. These studies proposed here will characterize a smooth muscle specific promoter which will allow us to deliver specific gene products into smooth muscle cells and study their role in SM-cell growth and differentiation.
| Zilberman, A; Dave, V; Miano, J et al. (1998) Evolutionarily conserved promoter region containing CArG*-like elements is crucial for smooth muscle myosin heavy chain gene expression. Circ Res 82:566-75 |
| Katoh, Y; Molkentin, J D; Dave, V et al. (1998) MEF2B is a component of a smooth muscle-specific complex that binds an A/T-rich element important for smooth muscle myosin heavy chain gene expression. J Biol Chem 273:1511-8 |
| White, S L; Zhou, M Y; Low, R B et al. (1998) Myosin heavy chain isoform expression in rat smooth muscle development. Am J Physiol 275:C581-9 |
| Katoh, Y; Loukianov, E; Kopras, E et al. (1994) Identification of functional promoter elements in the rabbit smooth muscle myosin heavy chain gene. J Biol Chem 269:30538-45 |
| Aikawa, M; Sivam, P N; Kuro-o, M et al. (1993) Human smooth muscle myosin heavy chain isoforms as molecular markers for vascular development and atherosclerosis. Circ Res 73:1000-12 |
