SGER: Cloning of G Protein-Coupled Steroid Receptors

马丁·J·凯利IBN-9500239类固醇激素在许多身体功能中发挥核心作用，包括神经发育、生殖、盐水动态平衡、对环境应激源的反应、骨骼维护和体重以及血压等。人们普遍认为，这些强大的激素的作用是通过与细胞内受体结合来发挥作用的，这些受体随后二聚化并结合到核DNA上，在那里它们起到促进或抑制基因转录的作用。这些行为通常需要几个小时到几天的时间才能显现出来。然而，一些电生理学和行为学研究已经报道了这些激素在几秒钟到几分钟的时间内非常迅速的影响。荷尔蒙的快速作用表明，核内作用部位的可能性很小，这与膜结合的G蛋白偶联受体的存在更为一致。凯利博士组建了一支技术娴熟的研究团队，他们在分子生物学、行为学和电生理学方面经验丰富，以分离和克隆这些雌激素和糖皮质激素的新型类固醇受体。利用最新的表达克隆策略，该小组建议分离和鉴定糖皮质激素和雌激素的G蛋白偶联受体，研究这些新受体在细胞代谢中的生理作用，确定其天然配体，并开始设计激动剂和拮抗剂用于未来的研究。这一建议适用于SGER奖，因为这些研究是新颖的，非常令人兴奋。此外，如果成功，这一结果将彻底改变我们对类固醇激素作用机制的理解，并在神经科学、内分泌学和行为学领域产生重大影响。

Martin J. Kelly IBN-9500239 Steroid hormones play central roles in many bodily functions including neural development, reproduction, salt and water homeostasis, response to environmental stressors, skeletal maintenance and grmwth, and blood pressure to mention a few. It is generally agreed that the actions of these powerful hormones are exerted by binding to intracellular receptors which subsequently dimerize and bind to nuclear DNA where they act to facilitate or inhibit gene transcription. These actions usually take hours to days to be manifested. However, several electrophysiological and behavioral studies have reported very rapid effects of these hormones, in the seconds to minutes time frame. The rapid action of the hormones suggest that a nuclear site of action is highly unlikely and is more consistent with the existence of membrane bound G-protein-coupled receptors. Dr. Kelly has assembled a team of skilled investigators, experienced in molecular biology, behavior and electrophysiology to isolate and clone these novel steroid receptors for estrogen and glucocorticoid hormones. Using the latest in expression cloning strategies, this group proposes to isolate and characterize G-protein coupled receptors for glucocorticoids and estrogen, to study the physiological role of these novel receptors in cellular metabolism, to identify their natural ligands and begin to design agonists and antagonists for future study. This proposal is appropriate for a SGER award because these studies are novel and highly exciting. Moreover, if successful, the outcome will revolutionize our understanding of the mechanism of steroid hormones action and have major impacts in the fields of neuroscience, endocrinology and behavior.