Atherosclerosis results, at least in part from the """"""""differentiation"""""""" of smooth muscle cells in that they proliferate, decrease the expression of contractile proteins, and accumulate lipid. To understand the modulation of smooth muscle cell differentiation the proposed research will isolate and characterize the gene that may have a key role in regulating smooth muscle cell development. This approach takes advantage of recent advances in studies of skeletal muscle development which have led to the isolation of master regulatory genes for this tissue. Three genes (MyoD1, myogenin and Myf-5) have been isolated that have the ability to convert non-muscle cell types to skeletal muscle when they are constitutively expressed with a viral promoter. Normally these genes are not expressed in smooth muscle or any other cell type and they appear to be specific for controlling the differentiation program of skeletal muscle. The three skeletal muscle determination genes share a region of homology that is also found in the myc and lyl oncogenes, tissue-specific transcription factors, and in genes that are important in Drosphila development. This motif, a basic region- helix-loop-helix structure, may be shared by a general family of molecules that are of critical importance in determining the developmental fates of many cell types. Probes to this highly conserved motif will be used to isolate homologous sequences from smooth muscle cDNA libraries. Clones of these cDNAs will be used to determine the tissue specificity of mRNA expression. Full length cDNAs for these smooth muscle factors will be isolated and subcloned into a eucaryotic activate the expression of smooth muscle-specific contractile proteins and to autoregulate the endogenous factor gene. Clones will also be tested for their ability to trans- activate the expression of the vascular a-smooth actin gene. These clones may provide powerful tools to analyze the control of smooth muscle differentiation.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL045345-03
Application #
3364364
Study Section
Special Emphasis Panel (SRC (BB))
Project Start
1990-07-01
Project End
1993-12-31
Budget Start
1992-05-01
Budget End
1993-12-31
Support Year
3
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Case Western Reserve University
Department
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
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Gorski, D H; LePage, D F; Patel, C V et al. (1993) Molecular cloning of a diverged homeobox gene that is rapidly down-regulated during the G0/G1 transition in vascular smooth muscle cells. Mol Cell Biol 13:3722-33
Vincent, C K; Gualberto, A; Patel, C V et al. (1993) Different regulatory sequences control creatine kinase-M gene expression in directly injected skeletal and cardiac muscle. Mol Cell Biol 13:1264-72
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Patel, C V; Gorski, D H; LePage, D F et al. (1992) Molecular cloning of a homeobox transcription factor from adult aortic smooth muscle. J Biol Chem 267:26085-90
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