In diabetes, the death of insulin-producing ?-cells in the pancreas by apoptosis leads to insulin dependence. Yet, the events that promote ?-cell death are still not fully understood. It is essential to increase our basic knowledge of the processes regulating ?-cell survival in order to develop novel and efficient therapies for diabetic patients. Evidence suggests that the female hormone, 17?-estradiol (estradiol), protects insulin production and prevents diabetes. Although estradiol acts primarily via two distinct estrogen receptors (ERs), ERa and ER?, the individual contributions of these ERs in protecting ?-cell survival have not been established. Our long-term goal is to determine how to protect insulin production in diabetic patients by modulating estrogen signaling pathways in a gender non-specific manner. Our objective for this application is to elucidate the respective roles played by ERa, ER?, and non-classical estrogen actions in ?-cell survival and insulin production in vivo, through the use of genetic mouse models. Based on the preliminary data we have generated, our hypothesis is that ERa protects ?-cell survival;whereas, ER? reduces ERa function and provokes ?-cell apoptosis. In order to test this hypothesis, we will first use a ?-cell ERa deficient mouse (?ERaKO) to demonstrate that selective elimination of ERa in ?-cells impairs insulin production and provokes diabetes. Next, we will study a ?-cell ER? deficient mouse (?ER?KO) to demonstrate that conversely, selective elimination of ER? in ?-cells improves insulin production and prevents diabetes. Finally, we will create a combined ?-cell specific ERa/ER? knockout mouse (?ERa?KO). Using this last model we will demonstrate that in absence of the classical ERa and ER? in ?-cells, estradiol protects insulin production and prevents diabetes via non-genomic actions involving a novel membrane ER. Through the proposed research - which is the first investigation of ERs in ?-cell survival in vivo - we plan to demonstrate that classical and non-classical estrogen receptors are important to ?-cell survival in vivo, and therefore represent viable targets for therapeutic intervention.
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