Joseph M. Miano, Ph.D.

Miano Lab Page

Joseph M. Miano, Ph.D. Associate Professor Interim Director, Aab CVRI j.m.miano@rochester.edu Primary Appointment: Department of Medicine in the Aab Cardiovascular Research Institute Secondary Appointment: Pathology and Laboratory Medicine GEBS Cluster Affiliation: PHD Pathways of Human Disease Aab Cardiovascular Research Institute of the University of Rochester School of Medicine and Dentistry 211 Bailey Road Rm. A210D West Henrietta, NY 14586 Phone: (585) 276-9789 Fax: (585) 276-9830

Dr. 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, Journal of Molecular and Cellular Cardiology, Physiological Genomics, Journal of Biological Chemistry, and Arteriosclerosis, Thrombosis and Vascular Biology. He is also a Fellow of the American Heart Association and member of the North American Vascular Biology Organization.

Research Overview

Perturbations in programs of cellular differentiation underlie numerous human ailments. Within the vasculature, for example, smooth muscle cells (SMC) exhibit phenotypic plasticity in which their normal differentiated program is subverted to one of growth, migration, and matrix secretion. This process of “de-differentiation” is thought to be an early event in the pathogenesis of vascular diseases. On the other hand, circulating vascular progenitor cells can “home” specifically to diseased vascular tissue and undergo subsequent SMC differentiation. The latter process may function to stabilize an otherwise rupture-prone, vulnerable atherosclerotic plaque. Thus, an understanding of the molecular underpinnings of SMC differentiation has enormous potential for treating and possibly limiting vascular diseases as well as other SMC-associated diseases (e.g., asthma, Alzheimer’s).

The focus of the Miano research program is to elucidate the transcriptional program(s) of normal SMC differentiation. Three inter-related projects are underway to address this global research endeavor. Project 1 tests the hypothesis that retinoids (pro-differentiating agents used in cancer therapy) ameliorate vascular diseases through the coordinate expression of key target genes. Several of these genes’ expression is compromised in the setting of vascular disease. We are particularly interested in the transcriptional control and function of a novel retinoid-inducible tumor suppressor called AKAP12, a new protease we call RISC, and an alpha integrin subunit. Project 2 tests the hypothesis that SMC-restricted gene expression is mediated by modular elements residing remotely from the core promoter. BAC recombineering and transgenic mouse/fish models are used in conjunction with various bioinformatics tools to define regulatory elements governing SMC differentiation in vivo. Project 3 tests the hypothesis that serum response factor and its coactivator myocardin orchestrate a program of SMC differentiation. Conditional knockouts, genome-wide analysis of target genes, and the role of these transcription factors in Alzheimer’s Disease are some of the current topics of investigation. These projects are necessarily multi-disciplinary and provide ample opportunities for trainees to embrace state-of-the-art technologies in genomics, genetics, bioinformatics, vascular pathobiology, and gene transcription control.

Recent Publications

1. Lee, T-H.D., Streb, J.W., Georger, M.A., Miano, J.M. Tissue expression of the novel serine carboxypeptidase Scpep1. J.Histochem.Cytochem., 54:701-711, 2006.
2. Sun, Q., Chen, G., Streb, J.W., Long, X, Yang, Y., Stoeckert, C.J., Jr., Miano, J.M. Defining the mammalian CArGome. Genome Res., 16:197-207, 2006.
3. Streb, J.W. and Miano, J.M. Cross-species sequence analysis reveals multiple charged residue-rich domains that regulate nuclear/cytoplasmic partitioning and membrane localization of A kinase anchoring protein 12 (SSeCKS/Gravin). J.Biol.Chem., 280:28007-28014, 2005.
4. Zlokovic, B.V., Deane, R., Sallstrom, J., Chow, N., Miano, J.M. Neurovascular pathways and Alzheimer amyloid b-peptide. Brain Pathol., 15:78-83, 2005.
5. Streb, J.W. and Miano, J.M. AKAP12 alpha: An atypical serum response factor-dependent target gene. J.Biol.Chem., 280:4125-4134, 2005.
6. Streb, J.W., Kitchen, C.M., Gelman, I.H. Miano, J.M. Multiple promoters direct expression of three AKAP12 isoforms with distinct tissue and subcellular distribution profiles. J.Biol.Chem., 279:56014-56023, 2004.
7. Miano, J.M., Ramanan, N., Georger, M.A., de Mesy Bentley, K.L., Emerson, R.L., Balza, R.O., Jr., Xiao, Q., Weiler, H., Ginty, D.D., Misra, R.P. Restricted inactivation of serum response factor to the cardiovascular system. Proc.Natl.Acad.Sci., USA., 101:17132-17137, 2004.
8. Miano, J.M. Serum response factor: toggling between disparate programs of gene expression. J.Mol.Cell.Cardiol., 35:577-593, 2003.
9. Chen, J., Chada, S., Mhashilkar, A., Miano, J.M. Tumor Suppressor MDA-7/IL-24 Selectively Inhibits Vascular Smooth Muscle Cell Growth and Migration. Mol. Ther., 8:220-229, 2003.
10. 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.
11. 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.
12. Miano, J.M., Georger, M.A., Rich, A., de Mesy Bentley, K.L. Ultrastructure of zebrafish dorsal aortic cells. Zebrafish, 3:455-463, 2006.
13. Miano, J.M., Long, X.C., Fujiwara, K. Serum response factor: master regulator of the actin cytoskeleton and contractile apparatus. Am.J.Physiol. Cell Physiol., 292:C70-C81, 2007.
14. Long, X. and Miano J.M. Remote control of gene expression. J.Biol.Chem., 282:15941-15945, 2007.
15. Chow, N., Bell, R.D., Deane R., Streb, J.W., Guo, H., Chen, J., Rubio, A., Brooks, A., Van Nostrand, W., Miano, J.M., and Zlokovic, B.V. Serum response factor and myocardin mediate arterial hypercontractility and cerebral blood flow dysregulation in Alzheimer’s phenotype. Proc.Natl.Acad.Sci., USA., 104:823-828, 2007.
16. Long X., Creemers, E.E., Wang, D-Z., Olson, E.N. and Miano, J.M. Myocardin is a bifunctional switch for smooth versus skeletal muscle differentiation. Proc.Natl.Acad.Sci., USA., 104:16570-16575, 2007.