application) Abnormal proliferation and phenotypic change of smooth muscle cells (SMC) have been associated with pathogenesis of congenital and acquired human vascular disease. However, little is understood about the molecular mechanisms that control SMC lineage determination, proliferation and differentiation during cardiovascular development. To address these questions, the investigators chose to characterize the regulation of SM22, a gene known to be a marker for adult smooth muscle, in the mouse. During embryogenesis, this gene is first expressed in all three muscle lineages, and then becomes restricted to all different types of SMCs. Surprisingly, the SM22 promoter is active only in a subset of arterial SMCs, not visceral, nor coronary, nor vena cava SMCs. Site directed mutagenesis of the SM22 promoter reveals that the proximal CArG box is required for its temporospatial expression in transgenic mice, suggesting that SRF (serum Responsive Factor), the CArG box binding protein, may play an important role in SM22 gene regulation. The overall goal of this proposal is to define the molecular mechanisms that discern the differential expression of the SM22 promoter in different subtypes of SMCs. The project will have two major aims, 1) to define the critical sequences in the proximal CArG box that required for specific activation of the promoter in arterial SMCs. 2) to define the cis-acting elements that confer specific expression of SM22 in SMC subtypes such as visceral and vena cava SMCs. These studies represent an important aspect of current vascular research in understanding the molecular mechanisms that control SMC proliferation, differentiation and lineage determination during cardiovascular development. Elucidation of the molecular mechanisms governing SMC differentiation and determination will open up a new frontier to develop molecular gene therapies for both congenital and acquired cardiovascular diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL058916-03
Application #
6183343
Study Section
Experimental Cardiovascular Sciences Study Section (ECS)
Project Start
1998-09-11
Project End
2003-08-31
Budget Start
2000-09-01
Budget End
2001-08-31
Support Year
3
Fiscal Year
2000
Total Cost
$275,715
Indirect Cost
Name
Wayne State University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Detroit
State
MI
Country
United States
Zip Code
48202
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Shen, Jianbin; Yang, Maozhou; Jiang, Hong et al. (2011) Arterial injury promotes medial chondrogenesis in Sm22 knockout mice. Cardiovasc Res 90:28-37
Yang, Maozhou; Jiang, Hong; Li, Li (2010) Sm22? transcription occurs at the early onset of the cardiovascular system and the intron 1 is dispensable for its transcription in smooth muscle cells during mouse development. Int J Physiol Pathophysiol Pharmacol 2:12-9
Shen, Jianbin; Yang, Maozhou; Ju, Donghong et al. (2010) Disruption of SM22 promotes inflammation after artery injury via nuclear factor kappaB activation. Circ Res 106:1351-62
Yang, L V; Wan, J; Ge, Y et al. (2006) The GATA site-dependent hemogen promoter is transcriptionally regulated by GATA1 in hematopoietic and leukemia cells. Leukemia 20:417-25
Qiu, Ping; Ritchie, Raquel P; Gong, Xue Qian et al. (2006) Dynamic changes in chromatin acetylation and the expression of histone acetyltransferases and histone deacetylases regulate the SM22alpha transcription in response to Smad3-mediated TGFbeta1 signaling. Biochem Biophys Res Commun 348:351-8
Qiu, Ping; Ritchie, Raquel P; Fu, Zhiyao et al. (2005) Myocardin enhances Smad3-mediated transforming growth factor-beta1 signaling in a CArG box-independent manner: Smad-binding element is an important cis element for SM22alpha transcription in vivo. Circ Res 97:983-91
Xu, Rui; Ho, Ye-Shih; Ritchie, Raquel P et al. (2003) Human SM22 alpha BAC encompasses regulatory sequences for expression in vascular and visceral smooth muscles at fetal and adult stages. Am J Physiol Heart Circ Physiol 284:H1398-407
Qiu, Ping; Feng, Xin Hua; Li, Li (2003) Interaction of Smad3 and SRF-associated complex mediates TGF-beta1 signals to regulate SM22 transcription during myofibroblast differentiation. J Mol Cell Cardiol 35:1407-20
Yang, Li V; Heng, Henry H; Wan, Junmei et al. (2003) Alternative promoters and polyadenylation regulate tissue-specific expression of Hemogen isoforms during hematopoiesis and spermatogenesis. Dev Dyn 228:606-16

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