Joseph M. Miano received his Ph.D. in Experimental Pathology from New York Medical College in 1992. His post-doctoral training was done in Eric Olson’s laboratory at the University of Texas M.D. Anderson Cancer Center where he cloned and characterized several smooth muscle-restricted promoters and initiated the study of retinoids in the vessel wall. Prior to his appointment at the U of R, Dr. Miano was an Assistant Professor in the Department of Physiology at the Medical College of Wisconsin. He serves on the Editorial Boards of Circulation Research, American Journal of Physiology Heart and Circulatory Physiology, and Journal of Molecular and Cellular Cardiology. His major research interests include smooth muscle cell growth and differentiation control with special emphasis on retinoid response genes in smooth muscle, transgenic mouse models, genomics, and bioinformatics.

Perturbations in normal smooth muscle cell (SMC) growth and differentiation control are central to the development of various vasculopathies including atherosclerosis, transplant arteriopathy, hypertension, and restenosis following procedural revascularization. Two major research initiatives are underway to explore both SMC growth and differentiation control.

1) RETINOIDS AND SMC BIOLOGY
Retinoids have been in clinical use for many years to treat a variety of hyper-proliferative disorders including several dermatopathologies and cancer. The Miano Lab was the first to show that all-trans retinoic acid inhibits SMC growth and vessel wall narrowing following experimental angioplasty. Further, this lab demonstrated functional retinoid receptors in cultured SMC from various arterial beds. Retinoid receptors are members of the nuclear receptor family of ligand-activated transcription factors, which alter the cellular transcriptome through changes in gene expression profiles (Fig. 1). A recently completed screen for retinoid response genes in vascular SMC revealed a novel retinoid-response gene set in SMC. Three of these genes are the focus of intense research in the Miano Lab. One gene is a new tumor suppressor called SSeCKS (a member of the AKAP family of proteins); a second gene is alpha 8 integrin which is highly restricted to SMC; a third gene is a novel one called RISC (retinoid-inducible serine carboxypeptidase). Each of these genes is being worked up from the genomics/promoter level to the functional level in an effort to understand how retinoids exert their favorable effects in the vessel wall and perhaps other pathologies as well.

2) GENOMICS AND TRANSGENESIS OF SMC
DIFFERENTIATION. The SMC differentiation program is often subverted in disease states. Thus, a major effort in the Miano Lab is devoted to understanding the normal transcriptional circuitry governing SMC differentiation through analyses of promoters that are preferentially active in SMC lineages. At MD Anderson Cancer Center, Dr. Miano helped develop and characterize the first transgenic mouse carrying a SMC-restricted promoter (Fig. 2). The SM22 promoter is currently being exploited in the Miano Lab for cell-specific gene targeting and cell-restricted knockouts in mice using the Cre-lox system. Another major project is the study of the SM-calponin promoter in transgenic mice that carry a bacterial artificial chromosome (BAC) harboring human SM-calponin. The Miano Lab uses both in silico and traditional wet-lab assays to "sift" through large genomic sequences of the BAC for evolutionarily-conserved regulatory modules controlling SM-calponin expression in vivo. They are particularly interested in several intergenic regulatory modules, including one that appears to be acting as an insulator.

A central transcription factor involved in SMC-restricted gene expression is serum response factor (SRF). Recently, the Miano Lab cloned a novel cofactor of SRF called myocardin, which potentiates the expression of several SMC differentiation genes (Fig. 3). Studies underway include an analysis of different SRF isoforms and myocardin in normal and diseased vascular tissues as well as the generation and characterization of mice made null for these genes in SMC. Finally, studies have been initiated in zebrafish, a versatile model system for the study of cardiovascular development and function, to study evolutionary concepts relating to vascular SMC differentiation.

In total, this laboratory uses computers, genomics, and transgenic animal systems to gain a better understanding of the genetic program for SMC differentiation. Once such information is in hand, questions pertaining to alterations in this program of gene expression during vascular disease can be addressed.

Chen, J., Kitchen, C.M., Streb, J.W., and Miano, J.M. Myocardin: a component of a molecular switch for smooth muscle cell differentiation. J.Mol.Cell.Cardiol. 34:1345-1356, 2002.

Miano, J.M., Kitchen, C.M., Chen, J., Maltby, K.M., Kelly, L.A., Weiler, H., Krahe, R., Ashworth, L.K., and Garcia, E. Human smooth muscle calponin expression in transgenic mice revealed with a bacterial artificial chromosome. Am.J.Physiol. Heart Circ.Physiol., 282:H1793-1803, 2002.

Miano, J.M., Carlson, M.A., Spencer, J.J., and Misra, R.P. Serum response factor-dependent regulation of the smooth muscle calponin gene. J. Biol. Chem., 275:9814-9822, 2000.

Chen, J., Streb, J.W., Maltby, K.M., Kitchen, C.M., and Miano, J.M. Cloning of a novel retinoid-inducible serine carboxypeptidase from vascular smooth muscle cells. J.Biol.Chem. 276:34175-34181, 2001.

Dulin, N.O., Orlov, S.N., Kitchen, C.M., Voyno-Yasenetskaya, T.A., and Miano, J.M. G protein-coupled receptor-activation of the smooth muscle calponin gene. Biochem.J., 357:587-592, 2001.

Miano, J.M., Thomas, S., and Disteche, C.M. Reversible expression and chromosomal mapping of the mouse smooth muscle calponin gene. Mamm. Genome. 12:187-191, 2001.

Ou, H., Haendeler, J., Aebly, M.R., Kelly, L.A., Cholewa, B.C., Koike, G., Kwitek-Black, A., Jacob, H.J., Berk, B.C., and Miano, J.M. Retinoic acid-induced tissue transglutaminase and apoptosis in vascular smooth muscle cells. Circ.Res., 87:881-887, 2000.

Miano, J.M. and Berk, B.C. Retinoids: Versatile biological response modifiers of vascular smooth muscle phenotype. Circ.Res., 87:355-362, 2000.

Miano, J.M., Carlson, M.A., Spencer, J.J., and Misra, R.P. Serum response factor-dependent regulation of the smooth muscle calponin gene. J.Biol.Chem., 275:9814-9822, 2000.