Control of Multidrug Transport Activity in Embryos

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The two main goals of this research are first, to understand the cell biological regulation of multidrug efflux transport and second, to probe the roles of these transporters in protection and regulation of embryonic development. This proposal links between two bodies of knowledge, one on the cellular physiology of multidrug efflux transport, primarily examined in the context of cancer and epithelial transport, and another focusing the structural changes in cell surface and membrane organization of embryo development. In the ROO Phase of this proposal, Hamdoun will continue and expand his investigation ofthe relationship between cell surface changes in early embryo development and changes in the efflux transporter activity focusing on sea urchins as an easily assayed and manipulated model organism. He will also continue efforts, currently ongoing in the K Phase of this award, to translate findings from the sea urchin to the mouse model, in order to characterize the role of these activity changes in protection of the embryo from potential teratogens encountered during assisted reproduction. Research in the K Phase of this award has revealed rapid upregulation of ABCB (pgp) and ABCC (mrp) efflux transporter activity following fertilization of sea urchin eggs and then later down-regualtion of efflux transport In a subset of 4 embryonic germline progenitor cells, known as the small micromeres. In most other systems, cycling of ABC transporters in and out of membranes is continuous, whereas in the sea urchin the two episodes of rapid change in efflux activity and cortical organization provide a powerful model for studying the cell structure and transporter function relationships. In Aims 1 and 2 Hamdoun will characterize the post-fertilization redistribution of Sp-ABCB1a (an ortholog of mammalian p-gp) activity by movement of the transporter to the tips of microvilli. In the third Aim, Hamdoun will extend these findings to the mouse model, specifically following up on his preliminary finding of loss of pgp transporter activity after fertilization of mouse oocytes and again he will focus on how activity changes relate to organization ofthe cortical actin cytoskeleton. In a new fourth Aim, Hamdoun will study the mechansims of transporter regulation in the small micromeres.