The overall goal of this research is to understand the cell biological regulation of multidrug efflux transport activity during early embryo development. This application links two bodies of knowledge, the functional physiology of multidrug efflux transport, primarily studied in the context of cancer and epithelial transport, and the structural changes in cell surface and membrane organization, primarily studied in the context of cell and developmental biology. In this application, the candidate will characterize the relationship between cell surface changes that occur in early embryo development and the concomitant changes in the efflux transporter activity in two model organisms, the sea urchin and the mouse. The cell biology side is to understand how transport activity can be rapidly changed by cell stimuli and especially the relationship between structure (movement to microvilli) and function (prevention of entry of toxicants into the cell). The developmental biology side is to understand how the membrane of the unfertilized egg is altered from one specialized to fuse with the sperm to one that now protects and regulates subsequent development. The candidate's postdoctoral research has revealed massive and rapid up-regulation of ABCB (pgp) and ABCC (mrp) efflux transporter activity following fertilization of sea urchin eggs. In most cells insertion of multidrug transporters into the membrane is continuous, whereas in the sea urchin this occurs rapidly after fertilization. Thus, the sea urchin provides a powerful model for studying this phenomenon. In the first two aims, the candidate will characterize the post-fertilization redistribution of Sp-ABCB1a (an ortholog of mammalian pgp) activity by movement of the transporter to the tips of microvilli (Aim 1) and the dynamics of Sp-ABCB1a localization in living embryos (Aim 2). Thereafter, he will extend these findings to the mouse model, specifically following up on the preliminary finding of loss of pgp transporter activity after fertilization of mouse oocytes (Aim 3).
| Shipp, Lauren E; Hill, Rose Z; Moy, Gary W et al. (2015) ABCC5 is required for cAMP-mediated hindgut invagination in sea urchin embryos. Development 142:3537-48 |
| Shipp, Lauren E; Hamdoun, Amro (2012) ATP-binding cassette (ABC) transporter expression and localization in sea urchin development. Dev Dyn 241:1111-24 |
| Gökirmak, Tufan; Campanale, Joseph P; Shipp, Lauren E et al. (2012) Localization and substrate selectivity of sea urchin multidrug (MDR) efflux transporters. J Biol Chem 287:43876-83 |
| Campanale, Joseph P; Hamdoun, Amro (2012) Programmed reduction of ABC transporter activity in sea urchin germline progenitors. Development 139:783-92 |
| Bosnjak, Ivana; Uhlinger, Kevin R; Heim, Wesley et al. (2009) Multidrug efflux transporters limit accumulation of inorganic, but not organic, mercury in sea urchin embryos. Environ Sci Technol 43:8374-80 |
