Smooth muscle cells (SMCs) in different tissues express distinct groups of proteins that give each tissue unique physiological properties. However, few studies have comprehensively defined the transcription regulatory networks that are responsible for these tissue-specific properties of SMCs. Experiments described in this proposal will begin to fill this gap in our knowledge by defining the transcription regulatory networks that direct gene expression in SMCs in different tissues of the GI tract. Unraveling these mechanisms is crucial for understanding the pathology of many intestinal diseases that are associated with altered contractility resulting from changes in expression of smooth muscle-specific proteins. Our preliminary studies have demonstrated that the telokin promoter provides a unique model system for the analysis of transcription factors that regulate gene expression, specifically in GI SMCs. We propose that Sox and SMAD proteins, which bind to the -190 to -90 region of the telokin promoter, collaborate with SRF and other factors that bind to the AT/CArG (-90 to -56) region, to drive telokin expression specifically in SMCs of the GI tract.
Three specific aims are proposed to test this hypothesis.
For Aim 1, the physiological roles of Sox and SMAD proteins in regulating telokin expression will be determined. In addition, the importance of the Sox and SMAD binding sites in the telokin promoter for expression in GI SMC in vivo will be confirmed. Our previous studies have identified several trans-acting factors that bind to the AT/CArG elements in the telokin promoter. Experiments described in Aim 2 will determine which of these factors cooperate with Sox and SMAD proteins to direct telokin gene expression in GI SMC. One of the proteins that binds to the AT/CArG region is Foxf1 and as published and preliminary data suggest that Foxf1 plays an important role in GI tract development, the function of this protein will be further investigated in mice harboring a smooth muscle-specific knockout of the gene (Aim 3). Together these studies will allow us to identify the transcription regulatory network that controls expression of contractile proteins in GI smooth muscle tissues. Future studies, will examine how expression of these transcription factors is altered in diseases that affect GI motility. This will allow us to link changes in specific transcription factors to altered expression of contractile proteins and subsequent altered contractility of diseased tissue. Project Narrative: The goal of our studies is to identify the transcription factors that control the differentiation state of gastrointestinal smooth muscle cells. The differentiation state of smooth muscle is altered, resulting in impaired contractility, in numerous pathological conditions such as Crohns disease, inflammatory bowel disease, idiopathic megacolon and Hirschsprungs disease. Identifying the transcription factors that are dysregulated is an essential step towards designing appropriate therapeutic agents to treat the motility defects that occur in these diseases.
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