Nuclear hormone receptors (NHRs) comprise a class of transcription factors that are involved in many biological processes, including dietary metabolism. Thus NHRs have proven to be attractive drug targets for the treatment of obesity and diabetes. The mechanisms by which NHRs function in living organisms are quite complex however, and many therapeutic approaches become ineffective due to drug resistance and undesirable side-effects. Through my work, I hope to enhance our understanding of how NHRs function in all aspects of development and homeostasis. This understanding would hopefully lead to the production of better NHR based therapies for diabetes, obesity, and other human maladies. My long-term strategy is to develop a system for characterizing NHR regulatory networks in vivo. In order to accomplish my goals I have chosen to use the roundworm C. elegans as a model organism for investigating NHRs. C. elegans provides several advantages for studying transcription factors in vivo, and for linking molecular functions to distinct physiological processes. I will observe and quantify NHR activity in live animals, and assess the contribution of regulatory factors to NHR activity. Additionally, I will use this system to discover the links between NHR function and physiological processes. In the period covered by this grant I will focus on adopting several skills that will be useful for setting up the system I described above. First, I will learn computer programming methods and chromatin immunoprecipitation techniques and adopt them to identify NHR target genes. Second, I will acquire expertise in worm physiology and anatomy and use this expertise to build GFP reporters with which I can visualize and quantify NHR regulation in vivo. Finally, I will learn to develop chemical extraction methods for the identification of small-molecule ligands that serve as regulators of C. elegans NHRs. The successful completion of the goals outlined in this proposal will greatly facilitate the initiation of an independent research lab that has the capacity to be immediately productive.
| Taubert, Stefan; Van Gilst, Marc R; Hansen, Malene et al. (2006) A Mediator subunit, MDT-15, integrates regulation of fatty acid metabolism by NHR-49-dependent and -independent pathways in C. elegans. Genes Dev 20:1137-49 |
| Van Gilst, Marc R; Hadjivassiliou, Haralambos; Jolly, Amber et al. (2005) Nuclear hormone receptor NHR-49 controls fat consumption and fatty acid composition in C. elegans. PLoS Biol 3:e53 |
| Van Gilst, Marc R; Hadjivassiliou, Haralambos; Yamamoto, Keith R (2005) A Caenorhabditis elegans nutrient response system partially dependent on nuclear receptor NHR-49. Proc Natl Acad Sci U S A 102:13496-501 |
