The GnRH system has fascinated both experimentalists and theoreticians because it has a frequency-dependent signal coding that maintains normal physiological function. Both the release and biosynthesis of the gonadotropins LH and FSH depend on the pattern of receptor stimulation. Under the previous funding we have made considerable progress in elucidating the mechanism of action of the agonist-GnRH receptor complex at the molecular level. In this renewal we will focus on the signal coding of the GnRHR, as reflected in the pattern of gene network activation. We have reconfigured our laboratory, methodologies, and collaborations towards this goal. As we enter the post-genome era, the application of physics- and mathematics-based analytical techniques may lead to the development of new paradigms. We have recruited researchers from diverse disciplines, including mathematics, physics, pharmacology and molecular biology, to pursue an integrated experimental and theoretical investigation of the signal coding of the GnRH receptor system. We propose that the gene response pattern represents a defined state of a signaling and genetic network and have developed new hypotheses about the basis for response specificity. We will use gene profiling techniques to generate a detailed and coherent dataset of the gene responses that occur following activation of the GnRHR. We will produce new reagents and analysis tools to further this objective, and will develop and test mathematical models of this signal transduction-genetic network. To accomplish this we will (1) quantitatively map the global gene responses through time following stimulation of the GnRHR, (2) develop a high density mouse gonadotrope cDNA array, (3) develop clustering tools optimized for time-course analyses, and (4) develop and test mathematical models correlating the pattern of receptor stimulation and pattern of gene induction. These parallel investigations are highly synergistic and may result in fundamental new insight into the mechanisms underlying signaling specificity of the GnRHR system.
Showing the most recent 10 out of 31 publications
