Control of efflux transporter activity by cell surface reorganization in embryos.

描述（由申请人提供）：本研究的总体目标是了解胚胎早期发育过程中多药物外排转运活性的细胞生物学调控。该应用程序连接了两个知识体系，多药物外排运输的功能生理学，主要在癌症和上皮运输的背景下研究，以及细胞表面和膜组织的结构变化，主要在细胞和发育生物学的背景下研究。在本申请中，候选人将描述发生在早期胚胎发育中的细胞表面变化与海胆和小鼠两种模式生物中外排转运体活性的伴随变化之间的关系。细胞生物学方面是了解运输活动如何被细胞刺激迅速改变，特别是结构（向微绒毛的运动）和功能（防止毒物进入细胞）之间的关系。发育生物学方面是了解未受精卵的膜是如何从专门与精子融合的膜转变为现在保护和调节后续发育的膜的。

DESCRIPTION (provided by applicant): 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).