Joseph M. Miano, Ph.D.
Associate Director - Aab Cardiovascular Research Institute
|Associate Professor - Department of Medicine, Aab Cardiovascular Research Institute|
|1992 | Ph.D. | Experimental Pathology | New York Medical College|
|1988 | M.S. | Experimental Pathology | New York Medical College|
|1986 | B.S. | Biology | SUNY College at Cortland|
Altered programs of cellular differentiation (or phenotypic adaptation) underlie most complex diseases. Within the vasculature, smooth muscle cells (SMC) exhibit phenotypic adaptation in which their normal differentiated program, defined as the expression of genes encoding for contractile/cytoskeletal proteins that assemble myofilaments (A), is subverted to one of growth, migration, and matrix secretion with concomitant loss in normal myofilament array (B). The latter occurs in such vascular complications as atherosclerosis or restenosis following balloon angioplasty (C). Current efforts are devoted to an understanding of the biology of six genes expressed in differentiated vascular SMC (A): serum response factor (SRF) and its potent coactivator, myocardin (MYOCD) which constitute a master switch for SMC gene expression; a direct target of this transcriptional switch called Leiomodin 1 (LMOD1); a tumor suppressor gene, AKAP12; and a novel long non-coding RNA we call SENCR (Smooth muscle and Endothelial cell enriched long Non Coding RNA). Several of these genes’ expression is attenuated in the setting of vascular disease although we recently have observed elevated expression of SMC differentiation genes in the setting of Alzheimer’s angiopathy.
A major effort in the lab is directed towards studying the transcriptional regulation of SMC gene expression. Gene promoters are cloned and assayed in vitro and ultimately in transgenic mice. Our transgenic mouse models of SMC gene promoters encompass conventional transgenic approaches using the bacterial lacZ reporter gene or large genomic sequences contained in bacterial artificial chromosomes (BACs). Panel D shows how mutating critical SRF-binding CArG boxes within a BAC nullifies a gene’s expression (depicted by absence of red stain). We currently are studying the function and regulation of human MYOCD in BAC transgenic mice. SMC-restricted promoters such as SM22α and MYH11 have been exploited in tissue-specific, tamoxifen-inducible knockout studies where we have inactivated Srf in adult blood vessels and shown profound reductions in lesion formation after acute injury (E). Recently, we have used deep sequencing of RNA (F) to discover SRF-dependent genes. The combination of next generation sequencing with bioinformatics (G) allows us to discover new target genes of potential importance in cardiovascular pathobiology. The completion of numerous genomes has greatly facilitated this analysis. Regulatory element discovery and identification of variants (SNPs) that may alter function is a major goal in the Miano Lab. One regulatory element we are particularly interested in is the CArG element, whose consensus sequence is CC(A or T)6GG (seqlogo in figure). The CArG element binds SRF, which “toggles” between disparate gene programs based on its association with a variety of cofactors, most notably MYOCD. Together SRF-MYOCD coordinate biochemical, structural, and physiological attributes of a differentiated SMC. We hypothesize that SRF-MYOCD activity is altered in vascular diseases leading to a compromise in expression of many CArG-containing genes such as those encoding for contractile/cytoskeletal proteins as well as long non-coding RNAs (H). The pipeline of discovery is repeated therefore with the evaluation of new genes and complexes in the setting of various diseases (I), followed by analysis of their promoters or gene knockout studies in mice to gain new insights into normal and pathological conditions of the blood vessel wall.
Our ideas and efforts span the spectrum from computer to DNA to cells to whole animals. We intend to elucidate the regulation of genes and/or their functions during normal or pathological processes involving, but not limited to, the cardiovascular system. The work in the Miano Lab is necessarily multi-disciplinary and provides ample opportunities for trainees to embrace state-of-the-art technologies in genomics, genetics, bioinformatics, vascular pathobiology, and gene transcription control.
- Expression and promoter analysis of a highly restricted integrin alpha gene in vascular smooth muscle.,Kitchen CM, Cowan SL, Long X, Miano JM., Gene. 513:82-89, 2013.
Miano's Suggested Links
Joseph Miano , PhD
University of Rochester
School of Medicine and Dentistry
601 Elmwood Ave, Box CVRI
Rochester, New York 14642
Senior Project Research Associate
|Former Lab Members|