Growth factor signaling systems play a central role in cellular physiology and have been implicated in a wide range of pathophysiologic responses. In the urogenital system, these conditions include benign prostatic hyperplasia and bladder hypertrophy resulting from obstructive uropathies. Because growth factors can elicit such profound changes in cellular responses, understanding the regulation of expression of these mediators should provide important insights into these adaptations. Transcriptional control mechanisms are thought to play a role in altering the levels of the growth factors expressed by the cells of the urogenital system. One class of transcription factors implicated in both the positive and negative regulation of growth factor genes is the C2H2 type of zinc finger factor. With more than 700 C2H2 zinc finger proteins in the human genome, this is a largely unexplored group of regulators. Some of the C2H2 zinc fingers are associated with conserved functional motifs, such as the SCAN domain. The SCAN domain is a highly conserved 84-residue dimerization motif that is found at the N-terminus of about 10% of C2H2 zinc finger proteins. An attractive possibility is that the domain generates combinatorial diversity within the SCAN family of proteins. Despite the large number of members in this family, remarkably little is known about the domain itself or the functions of most of the proteins defined by the domain. However, some members of the family have been implicated in the regulation of growth and survival factors and preliminary studies suggest that SCAN family members are expressed by some of the cells of the urogenital system. The central hypothesis of this developmental project is that members of the SCAN-ZFP transcription factor family play a key role in the regulation of genes important in tissue renewal in the genitourinary tract. To further investigate this hypothesis, we propose two specific aims to define the relevant SCAN family members and the genes they regulate:
Specific Aim 1 : Characterize the spatial and temporal expression pattern of selected SCAN-ZFP in the urogenital system;
Specific Aim 2 : Identify candidate target genes in the genitourinary tract that are transcriptionally regulated by SCAN-ZFP. Collectively, these studies should provide new information about the SCAN family and its target genes in the urogenital system.
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