Biomedical Sciences Graduate Program(s)
Molecular Medicine
Biochemistry, Molecular Biology and Genetics
Molecular Cell and Developmental Biology
Research Description
· Molecular Regulation of Smooth Muscle Cell Differentiation in Development and in Disease
There is clear evidence that abnormal control of the differentiated state of the smooth muscle cell (SMC), or SMC phenotypic switching, plays a critical role in development of a number of major human diseases including atherosclerosis, hypertension, asthma, and cancer. However, the mechanisms and factors that regulate SMC phenotypic switching in these diseases are poorly understood. A major long-term goal of our laboratory has been to elucidate cellular and molecular mechanisms that control the growth and differentiation of SMC during normal vascular development, and to determine how these control processes are altered in disease states [see review by Owens et al. (1) ]. Current studies are focused on identifying molecular mechanisms that control the coordinate expression of genes such as smooth muscle α–actin (SM a -actin), SM22 a , and smooth muscle myosin heavy chains (SM MHC) that are required for the differentiated function of the SMC. Studies involve use of a wide repertoire of molecular-genetic techniques and include identification of cis elements and trans regulatory factors that regulate cell-type specific expression of SMC differentiation marker genes both in cultured cell systems and in vivo in transgenic mice. In addition, we use a variety of gene knockout, mouse chimeric, and gene over-expression approaches to investigate the role of specific transcription factors and local environmental cues (e.g. growth factors, mechanical factors, cell-cell and cell-matrix interactions, etc.) in regulation of SMC differentiation in vivo during vascular development, or in association with vascular injury or cardiovascular disease (2) . A particularly exciting recent development is that we have employed SMC specific promoters originally cloned and characterized in our laboratory to create mice in which we can target knockout (or over-expression) of genes of interest specifically to SMCs. Such systems permit development of unique and powerful genetic mouse model systems with which to directly explore mechanisms that contribute to vascular development in vivo, as well as to investigate the etiology of a variety of major cardiovascular diseases including atherosclerosis. In addition, we have completed studies investigating the role of epigenetic mechanisms in control of SMC differentiation and phenotypic switching (3) , as well as lineage determination of all cell types from embryonic stem cells (4) . We have also developed methods for producing purified populations of SMC or SMC progenitor cells from both embryonic and somatic stem cells for purposes of tissue regeneration and/or correcting gene defects that contribute to SMC-related diseases. Finally, we have recently obtained evidence showing that pro-inflammatory cytokines induce profound phenotypic switching of SMC, including not only down-regulation of SMC marker genes such as SM a -actin and SM MHC, but also marked activation of NF k B, and matrix metalloproteinases. These studies are extremely exciting in that they may provide insights into mechanisms that regulate the stability of the fibrous cap of advanced atherosclerotic plaques, and the probability they will rupture and initiate a heart attack. We are in the process of developing small molecule inhibitors to disrupt these pathways, with the goal of identifying exciting new therapies to prevent or reduce the chance atherosclerotic plaque rupture and a heart attack, which account for nearly 50% of all deaths in this country.
Selected Publications
Gan Q.; Yoshida T; McDonald OG.; Owens GK. (2007) Epigenetic Mechanisms Contribute to Pluripotency and Cell Lineage Determination of Embryonic Stem Cells. Stem Cells 25:2-9.
McDonald OG, Wamhoff BR, Hoofnagle MH, Owens GK. Control of SRF binding to CARG-box chromatin regulates smooth muscle gene expression in vivo. (2006) J Clin. Invest. 116:36-48.
Owens GK, Kumar MS, Wamhoff BR (2004) Molecular regulation of vascular smooth muscle cell differentiation in development and disease. Physiol. Reviews 84:767-801.
Wamhoff BR, Hoofnagle MH, Burns A, Sinha S, McDonald OG and Owens GK. (2004) A G/C element mediates repression of the SM22 α promoter within phenotypically modulated smooth muscle cells in experimental atherosclerosis. Circ Res95: 981-988.
Link to Other PubMed Listings for this Mentor
Intranet Profile
| Contact Information |
| |
Office Address: |
PO Box 801394, Robert M. Berne Cardiovascular Research Ce, |
| |
Office Phone: |
+1 434-924-2652, +1 434-924-9173 |
| |
Fax Phone: |
+1 434-982-0055 |
| |
Home Phone: |
+1 434-973-7707 |
Other Web sites for this mentor:
http://www.healthsystem.virginia.edu/internet/mstp/director.cfm
(Find Out How to Update Your Faculty Profile)
|
