Membrane estrogen receptors and ingestive behavior

描述（由申请人提供）：雌二醇（E2）在维持适当的能量和流体稳态中起着至关重要的作用。E2的关键作用在E2水平降低、肥胖、肥胖相关疾病和高血压风险升高的绝经后妇女中尤为明显。不幸的是，E2调节能量和体液平衡的机制仍然知之甚少。啮齿类动物研究表明，雌激素通过激活经典雌激素受体亚型(雌激素受体？(呃? ?)。呃? ?定位于细胞核，通过与DNA上的反应元件相互作用来改变基因表达。最近发现的ER?？也可以与细胞膜结合并作为表面受体，从而使人们认识到该受体可以通过替代的非传统机制影响基因表达，包括激活转录因子，如cAMP反应元件结合蛋白（CREB）。我们实验室最近的研究表明，膜相关雌激素受体（mER）的激活会减少食物和水的摄入量。因此，该提案旨在提供液体摄入，细胞间信号传导和病毒介导的遗传操作领域的培训，以增强候选人在雌激素调节食物摄入领域的现有优势。这将是

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.