Vascular smooth muscle cells are a vital component of the blood vessel wall, possessing extraordinary adaptive abilities. These cells display a range of phenotypes that are dependent upon the selective utilization of transcriptional programs. While smooth muscle modulation is essential for normal blood vessel function, their adaptive abilities are adversely associated with the pathologies of vascular occlusion diseases. Consequently, the molecular mechanisms governing gene transcription leading to resultant phenotypes are both biologically and clinically relevant. As an inroad to elucidating critical features that control smooth muscle transcription, our studies are focused on the development and differentiation of precursor cells into mature smooth muscle. Differentiation is accompanied by the orchestrated activation of a precise set of genes required for contraction. Though definitive regulatory elements and corresponding transcription factors are recognized to have a role in differentiation, how they are coupled to signals that convey selective gene expression is not well understood. We hypothesize that extracellular signals, like transforming growth factor-beta (TGF-?), use a distinct combination of intracellular pathways and transcription factors to impart smooth muscle-restricted expression. TGF-? has emerged as primary candidate for governing smooth muscle cell phenotypes.
The aims of this proposal are designed to employ the smooth muscle-specific expression of the cysteine-rich protein 1 (CRP1) gene to investigate the cis-acting elements, and trans- acting factors that convey selective transcriptional activity in response to defined signaling events. We have identified a unique regulatory region of the CRP1 gene that drives expression exclusively in arterial smooth muscle cells. We intend to use this regulatory element to characterize essential transcriptional pathways important for the expression of the CRP1 gene in differentiated smooth muscle cells.
The specific aims are: 1) To define the transcriptional mechanisms underlying the activation of the CRP1 gene by transforming growth factor-beta-1 (TGF-?1). 2) To determine the relationship between the functional activity of serum response factor (SRF), and signaling events that govern smooth muscle gene expression. 3) To unequivocally determine the necessity of the CArG element for expression of CRP1 by targeted mutagenesis. These studies are significant, as they will extend beyond the analysis of the transcriptional regulators, and determine the exact pathways that mediate transactivation, to address fundamental questions regarding the manifestation of smooth muscle cell phenotypes. ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL076428-01A2
Application #
7048321
Study Section
Cardiovascular Differentiation and Development Study Section (CDD)
Program Officer
Lin, Michael
Project Start
2006-02-01
Project End
2011-01-31
Budget Start
2006-02-01
Budget End
2007-01-31
Support Year
1
Fiscal Year
2006
Total Cost
$292,167
Indirect Cost
Name
Georgia Health Sciences University
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
966668691
City
Augusta
State
GA
Country
United States
Zip Code
30912
Zhao, Ning; Liu, Hua; Lilly, Brenda (2012) Reciprocal regulation of syndecan-2 and Notch signaling in vascular smooth muscle cells. J Biol Chem 287:16111-20
Wang, Qingqing; Zhao, Ning; Kennard, Simone et al. (2012) Notch2 and Notch3 function together to regulate vascular smooth muscle development. PLoS One 7:e37365
Pajaniappan, Mohanasundari; Glober, Nancy K; Kennard, Simone et al. (2011) Endothelial cells downregulate apolipoprotein D expression in mural cells through paracrine secretion and Notch signaling. Am J Physiol Heart Circ Physiol 301:H784-93
Liu, Hua; Zhang, Wenbo; Kennard, Simone et al. (2010) Notch3 is critical for proper angiogenesis and mural cell investment. Circ Res 107:860-70
Lilly, Brenda; Clark, Kathleen A; Yoshigi, Masaaki et al. (2010) Loss of the serum response factor cofactor, cysteine-rich protein 1, attenuates neointima formation in the mouse. Arterioscler Thromb Vasc Biol 30:694-701
Liu, Hua; Kennard, Simone; Lilly, Brenda (2009) NOTCH3 expression is induced in mural cells through an autoregulatory loop that requires endothelial-expressed JAGGED1. Circ Res 104:466-75
Lilly, Brenda; Kennard, Simone (2009) Differential gene expression in a coculture model of angiogenesis reveals modulation of select pathways and a role for Notch signaling. Physiol Genomics 36:69-78
Liu, Hua; Chen, Bo; Lilly, Brenda (2008) Fibroblasts potentiate blood vessel formation partially through secreted factor TIMP-1. Angiogenesis 11:223-34
Snider, Paige; Fix, Jana L; Rogers, Rhonda et al. (2008) Generation and characterization of Csrp1 enhancer-driven tissue-restricted Cre-recombinase mice. Genesis 46:167-76