Abstract

This is a revised application which proposes to study the transcriptional regulation of smooth muscle myosin heavy chain (SM MHC) gene expression. It is expected that through an understanding of the control of transcription of the SM MHC gene which is required in part for the differentiated function of the smooth muscle cell we will learn more about the molecular mechanisms that control the differentiation and/or maturation of smooth muscle cells. Alterations in the differentiated state of smooth muscle cells is thought to play a key role in the development and/or progression of post-angioplasty restenosis and/or atherosclerosis. There are three specific aims as follows:
Aim 1 of this proposal will be to identify cellular and molecular mechanisms that regulate cell-type specific expression of the SM MHC gene in vascular SMC in transgenic mice.
Aim 2 will be to identify trans acting factors that interact with and regulate the activity of cis elements shown to be important in the SMC-specific regulation of the SM MHC gene identified in aim 1 with a particular emphasis on factors that bind to novel cis regulatory elements of the SM MHC gene or with SM MHC cis elements such as the CArGs that have been shown to be important in the regulation of multiple SMC differentiation genes.
Aim 3 will be to determine mechanisms responsible for altered expression of SM MHC in SMC within intimal lesions from experimental animal models of vascular injury/post-angioplasty restenosis as well as in human atherosclerotic lesions. The proposed studies represent an extension of the Principal Investigator's ongoing work and will contribute to an understanding of the mechanisms that alter the control of SMC differentiation in atherogenesis and may lead to the identification of possible new interventional therapies. In addition these studies are likely to identify DNA regulatory sequences that confer SMC specific expression that could be used for construction of vectors for SMC specific gene knockouts and/or targeting gene therapies to the vasculature.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37HL057353-03
Application #
6184265
Study Section
Pathology A Study Section (PTHA)
Project Start
1998-04-01
Project End
2003-03-31
Budget Start
2000-04-01
Budget End
2001-03-31
Support Year
3
Fiscal Year
2000
Total Cost
$251,030
Indirect Cost

  Institution

Name
University of Virginia
Department
Physiology
Type
Schools of Medicine
DUNS #
001910777
City
Charlottesville
State
VA
Country
United States
Zip Code
22904

  Publications

Baylis, Richard A; Gomez, Delphine; Owens, Gary K (2017) Shifting the Focus of Preclinical, Murine Atherosclerosis Studies From Prevention to Late-Stage Intervention. Circ Res 120:775-777
Wu, Jing; Montaniel, Kim Ramil C; Saleh, Mohamed A et al. (2016) Origin of Matrix-Producing Cells That Contribute to Aortic Fibrosis in Hypertension. Hypertension 67:461-8
Bennett, Martin R; Sinha, Sanjay; Owens, Gary K (2016) Vascular Smooth Muscle Cells in Atherosclerosis. Circ Res 118:692-702
Gomez, Delphine; Owens, Gary K (2016) Reconciling Smooth Muscle Cell Oligoclonality and Proliferative Capacity in Experimental Atherosclerosis. Circ Res 119:1262-1264
Tabas, Ira; García-Cardeña, Guillermo; Owens, Gary K (2015) Recent insights into the cellular biology of atherosclerosis. J Cell Biol 209:13-22
Gomez, Delphine; Swiatlowska, Pamela; Owens, Gary K (2015) Epigenetic Control of Smooth Muscle Cell Identity and Lineage Memory. Arterioscler Thromb Vasc Biol 35:2508-16
Hoofnagle, Mark H; Neppl, Ronald L; Berzin, Erica L et al. (2011) Myocardin is differentially required for the development of smooth muscle cells and cardiomyocytes. Am J Physiol Heart Circ Physiol 300:H1707-21
Thomas, James A; Deaton, Rebecca A; Hastings, Nicole E et al. (2009) PDGF-DD, a novel mediator of smooth muscle cell phenotypic modulation, is upregulated in endothelial cells exposed to atherosclerosis-prone flow patterns. Am J Physiol Heart Circ Physiol 296:H442-52
Deaton, Rebecca A; Gan, Qiong; Owens, Gary K (2009) Sp1-dependent activation of KLF4 is required for PDGF-BB-induced phenotypic modulation of smooth muscle. Am J Physiol Heart Circ Physiol 296:H1027-37
Yoshida, Tadashi; Gan, Qiong; Owens, Gary K (2008) Kruppel-like factor 4, Elk-1, and histone deacetylases cooperatively suppress smooth muscle cell differentiation markers in response to oxidized phospholipids. Am J Physiol Cell Physiol 295:C1175-82

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