Glucocorticoids are crucial for the integrity and the function of the central nervous system function, for metabolic homeostasis and for preventing an over-reaction of the immune system. They bind to and activate the glucocorticoid receptor (GR). Most of GR -- mice, die within a few hours after birth because of respiratory failure.
To circumvent this problem and to analyse in detail the function of the GR in a given cell type, I propose to apply a tissue targeted gene disruption approach, which would use the Cre recombinase/loxP system. I have flanked the, third GR-exon with loxP sites, thus, it should be deleted when Cre is present in a cell. By using mice expressing cre in brain neurons, T Iymphocytes or macrophages we would expect a specific GR gene disruption in those cell types. | I expect defects in behavioral, T cell population and inflammation responses, respectively.
We propose to develop an inducible gene disruption system in mice. When fused with a mutated hormone binding domain of the progesterone receptor, cre recombinase responds to RU 486 but not to endogenous steroids. We can therefore induce recombination in cell culture. We will express this fusion protein in mice and see whether by injecting RU 486 we can induce recombination in vivo.