Membrane estrogen receptors and ingestive behavior

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DESCRIPTION (provided by applicant): Estradiol (E2) plays a crucial role in the maintenance of proper energy and fluid homeostasis. This key role of E2 is especially apparent in postmenopausal women who have decreased E2 levels and are at an elevated risk for obesity, obesity-related diseases, and hypertension. Unfortunately, the mechanism by which E2 regulates energy and fluid balance is still poorly understood. Rodent studies indicate that estrogens decrease food and water intake through a genomic mechanism via activation of the classical estrogen receptor subtype, estrogen receptor ? (ER??). ER?? localizes to the cell nucleus, where it alters gene expression by interacting with responsive elements on DNA. The more recent discovery that ER?? also can associate with the cell membrane and act as a surface receptor led to the appreciation that this receptor can affect gene expression through alternate, non-traditional mechanisms including activation of transcription factors such as cAMP response element binding protein (CREB). Recent studies from our laboratory demonstrate that activation of membrane-associated estrogen receptors (mER) decrease food and water intake. Accordingly, this proposal was designed to provide training in the areas of fluid intake, intercellular signaling and viral mediated genetic manipulations in addition to enhance the existing strengths of the candidate in the area of estrogen modulation of food intake. This will be accomplished, in part, by performing the proposed experiments that test the overarching hypothesis that mER decreases food and water intake by engaging intracellular signaling pathways traditionally associated with transcriptional changes. To this end, the experiments in this proposal include two aims, the first of which will test the requirement of metabotropic glutamate receptors (mGluR) in mediating the effects of mER on food and water intake. The second aim will examine food and water intake following knockdown of mER through AAV manipulation. Next this set of experiments will test for physical interactions between mER?? and mGluR and will test the role of mGluR on the intracellular effects of E2. In addition to providing important training to the candidate that will help her transition to a career as an independent scientist, the proposed research has the potential to increase the understanding of the mechanisms by which E2 signaling influences food and water intake and has the potential to reveal more general principals of steroid effects on gene expression.