This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator. The objective of the research in my laboratory is to dissect the cellular activities of NR4A NRs in the genetic model organism C. elegans. The cellular activities of NR4A, including mechanisms of transcriptional regulation and interactions with signal transduction pathways, are poorly understood. We have identified an organogenesis function for the C. elegans NR4A ortholog, NHR-6, in C. elegans. The INBRE funded project in my laboratory has two primary objectives: test the hypothesis that NHR-6 functions as an organ specific regulator of cell cycle progression and cell differentiation; and 2) to identify the cellular mechanisms of NHR-6 activity. Data from this work provide key insight into the functions of this group of physiologically and developmentally important proteins with emerging human health relevance. We are testing the cell proliferation and cell differentiation hypothesis using a tissue-specific microarray approach to identify the genes regulated by NHR-6. To date we have accomplished the generation of the animal transgenic reagents necessary for the study and the microarray analysis will be performed within the next two months. We are also initiating a series of genetic studies to identify interactions of NHR-6 with cell cycle regulators to determine the specific cell cycle regulatory function of NHR-6. The second objective is being pursued utilizing cell culture transcription assays to perform structure/function studies of NHR-6. This analysis will be combined with in vivo experiments to identify biologically relevant sites of protein interaction in NHR-6. In the past year, INBRE funds have been utilized to establish a new tissue culture facility in the ULM Biology department and we have validated the NHR-6 transcription assays in HEK 293 cells. Further optimization of the assays is ongoing and the structure/function experiments have been initiated.
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