Projects
22: Signaling of estrogenic endocrine disruptors through membrane-associated receptors.
New biosensors for endocrine disruptors.
Endocrine disruptors act via a variety of different receptor proteins on the cellular level. Very few studies have explored the actions of estrogenic chemicals through cell membrane-associated receptors. Here, a set of yeast strains will be developed as biosensors for such effects.
Picard Didier, Université de Genève
e-mail: picard@cellbio.unige.ch
Background
The physiological effects of estrogenic endocrine-disrupting chemicals are the result of combined action via a variety of different receptor proteins on the cellular level. While their effects through intracellular estrogen receptors have been extensively studied, far less is known about effects mediated by receptors associated with the cell membrane. A simple model organism such as baking yeast allows the dissection of multiple signalling pathways. Indeed, yeast has long been established as a ‘living test tube’ for human hormones and proteins.
Aim
In this project we will exploit baking yeast as a simplified assay system to separate the different signalling pathways from each other. We will focus on the two best-characterized membrane-associated signalling pathways of estrogens. The G-protein-coupled receptor GPR30 and the membrane-associated fractions of the nuclear estrogen receptors represent two completely different receptor classes.
We will engineer a set of yeast biosensor strains for these two pathways. With a simple luminometric analytical tool we will survey the pathway-specific activities of a series of endocrine disruptors and explore the possibility of high-throughput screens. Signalling of endocrine disruptors through these alternate pathways is likely to have physiological effects different from those mediated by nuclear estrogen receptors. We will therefore validate hits obtained with the yeast sensor strains with human cells, and compare the effects of GPR30 signalling of estrogen and of a representative endocrine disruptor on the expression of all genes in human cells.
Significance
Our simple biosensors for estrogenic chemicals acting through membrane-associated receptors will constitute novel screening tools and will help to gain insights in an area that has so far been neglected in research on endocrine disruptors.