Functional significance of hox genes in the epididymis

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Dr. Daniela Bomgardner is committed to an academic career. , focusing on basic research in reproductive medicine with the goal of being an independent investigator. Her current training has broadened her knowledge in cellular and molecular physiology of the reproductive tract. The KO8 will provide a unique opportunity for her to learn more advanced methods in molecular and cellular biology and to become more proficient and experienced in experimental planning and critical data analysis. The Department of Urology is dedicated to the candidate's research development and is committed to ensure protected time for research. The combination of the sponsors productive laboratory, the molecular and cellular core facilities at UVA, and the collaboration with Dr.'s H. Scrable and S. Zeitlin (Dept. Neuro-science, UVA) provides and excellent environment for learning new research techniques and approaches to scientific problems. Importantly, the candidates advisory committee, composed of established investigator with pertinent but diverse areas of expertise, and is strongly supportive of this project. Moreover, the expertise of Dr. B. Hinton (Dept. of Cell Biology, UVA) and Dr. M. Wilkinson (Dept. of Immunology, M.D. Anderson Cancer Center, Houston, TX) will provide additional support for the candidate's goal of becoming an independent investigator. The long-term objective of this proposal is to discover the mechanism underlying the development and maintenance of segmental function in the epididymis. Sperm maturation in the epididymis requires epithelial gene products expressed in a region-specific pattern. Our hypothesis is that hox genes are master regulators of this process. These genes are known to be crucial in segmental patterning of the embryo, but adult function of these genes is unknown. Specifically, it is proposed to develop a conditional mutation of the endogenous hoxa-11 gene. It is hypothesized that the down-regulation pathway of hoxa-11 includes Meis 1 as a DNA-binding cofactor and L1-CAM as a potential target. The gene and protein expression pattern of each participant in this pathway will be analyzed. The resulting data will be used as a baseline to test the hypothesis that temporal regulation of hoxa-11 influences critical periods in development and adult epididymal function. Finally, the hypothesis, that specific 5' hox genes can transactivated particular downstream targets together with DNA-binding factors will be investigated. A broad spectrum of modern research techniques will be used including state-of- the-art in vivo experiments. Findings from this proposal will provide fundamental information for the understanding of basic biological processes important in certain forms of male infertility and in certain urological dysplasias in pediatric urology.