Altered contractile protein expression and increased smooth muscle cell proliferation are characteristics of many vascular and pulmonary diseases. The long-term goal of this proposal is to unravel the mechanisms regulating the expression of smooth muscle-specific expression of telokin, a small myosin binding protein, will be elucidated. The overall hypothesis to be evaluated is that binding of tissue-specific nuclear proteins to cis-acting elements in the telokin promoter, regulates telokin transcription in smooth muscle. A corollary of this hypothesis is that the differential expression of telokin in visceral and vascular smooth muscle, results from either different levels of nuclear regulatory proteins or form unique nuclear proteins in each of the smooth muscle tissues.
Four Specific Aims are proposed to address this hypothesis. Experiments will first determine if telokin expression is restricted to smooth muscle cells throughout development, and determine the temporal pattern of telokin expression relative to other smooth muscle-specific proteins. The cis-acting elements in the telokin promoter that regulate telokin expression in smooth muscle tissues will be identified in cultured cells and in transgenic mice. The factors that bind to important regulatory elements will then be identified and cloned. Once regulatory factors have been cloned, their tissue and developmental pattern of expression will be analyzed and their role in regulating the expression of telokin and other smooth muscle genes determined. These studies will help unravel the complex network of interactions that ultimately results in smooth muscle differentiation and provide reagents that can be used to design smooth muscle-specific gene delivery systems.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL058571-04
Application #
6389694
Study Section
Pathology A Study Section (PTHA)
Program Officer
Applebaum-Bowden, Deborah
Project Start
1998-04-01
Project End
2002-03-31
Budget Start
2001-04-01
Budget End
2002-03-31
Support Year
4
Fiscal Year
2001
Total Cost
$251,811
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Physiology
Type
Schools of Medicine
DUNS #
005436803
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Zhou, Jiliang; Zhang, Min; Fang, Hong et al. (2009) The SWI/SNF chromatin remodeling complex regulates myocardin-induced smooth muscle-specific gene expression. Arterioscler Thromb Vasc Biol 29:921-8
Herring, B Paul; Zhou, Jiliang (2007) mCAT got youR TEF? Circ Res 101:856-8
Zhang, Min; Fang, Hong; Zhou, Jiliang et al. (2007) A novel role of Brg1 in the regulation of SRF/MRTFA-dependent smooth muscle-specific gene expression. J Biol Chem 282:25708-16
Touw, Ketrija; Hoggatt, April M; Simon, Gina et al. (2007) Hprt-targeted transgenes provide new insights into smooth muscle-restricted promoter activity. Am J Physiol Cell Physiol 292:C1024-32
Yin, Feng; Hoggatt, April M; Zhou, Jiliang et al. (2006) 130-kDa smooth muscle myosin light chain kinase is transcribed from a CArG-dependent, internal promoter within the mouse mylk gene. Am J Physiol Cell Physiol 290:C1599-609
Herring, B Paul; El-Mounayri, Omar; Gallagher, Patricia J et al. (2006) Regulation of myosin light chain kinase and telokin expression in smooth muscle tissues. Am J Physiol Cell Physiol 291:C817-27
El-Mounayri, Omar; Triplett, Jason W; Yates, Charles W et al. (2005) Regulation of smooth muscle-specific gene expression by homeodomain proteins, Hoxa10 and Hoxb8. J Biol Chem 280:25854-63
Zhou, Jiliang; Herring, B Paul (2005) Mechanisms responsible for the promoter-specific effects of myocardin. J Biol Chem 280:10861-9
Yin, Feng; Herring, B Paul (2005) GATA-6 can act as a positive or negative regulator of smooth muscle-specific gene expression. J Biol Chem 280:4745-52
Triplett, Jason W; Herring, B Paul; Pavalko, Fredrick M (2005) Adenoviral transgene expression enhanced by cotreatment with etoposide in cultured cells. Biotechniques 39:826, 828, 830, passim

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