Mechanisms of Response to GnRH Receptor Signaling

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DESCRIPTION (provided by applicant): The candidate has a broad training background in molecular biology and in animal model systems for the study of gene expression and endocrinology, including transgenic mice, rats, and hamsters. The candidate has training in all molecular biology techniques and has published manuscripts utilizing them. The training background includes virology, cellular and molecular biology, analysis of DNA-protein and protein- protein interactions, gene transcription, mRNA translation, and signal transduction. In vivo techniques include the creation and analysis of transgenic mice, tissue and organ analysis of mice, rats and hamsters, hormone replacement, dose-response assay paradigms, minor surgical procedures, immunohistochemistry, organotypic culture. Past awards include an independent R03 award and three prestigious postdoctoral fellowships. The environment provides an exceptional atmosphere for career development and further training. The candidate is a member of a U54 center, serving as a project co- investigator, and was recently awarded an R0l. He interacts with both basic science and clinical research faculty in his and other departments. His department has committed laboratory space in a modern, well equipped six year old facility, and he will move to a new expanded facility, that will open in 2003. The candidate's immediate goals are to increase laboratory personnel, to meet the scientific goals set out in the current R0l in support of renewal of that award, to initiate new research projects with the aim of supporting a successful application for a second R0l, and to achieve promotion to a tenured Associate Professor in the approximate time frame of this award. Although the candidate seeks relief from formal teaching and administrative duties normally required for progression to a tenured appointment, the candidate has a strong desire to provide an excellent training environment for graduate and postdoctoral level students. The candidate also seeks relief of salary burden on his current funding to support new laboratory personnel. The candidate proposes to initiate studies on the effects of pulsatile gonadotropin- releasing hormone on the translational and transcriptional regulation of gene expression. The candidate presents the hypothesis that releasing hormone modulates both transcriptional and non-transcriptional changes in gene expression and cell metabolism, and therefore regulates both short term and long term changes in gene transcription and mRNA utilization. Expanded aims are directed at understanding the modulation of pulsatile hormone stimulation by other endocrine effectors, such as insulin, growth factors, and gonadal steroids. Techniques to be applied to this problem include the use of the gonadotrope cell lines and primary pituitary cells for in a perifusion system, allowing the manipulation of the pulsatile regime. Isolation of actively translated and total mRNA from treated and control cells will allow identification and quantification of global changes in gene expression.