RUI: Mechanisms of Modulation of GABA(A) receptors by Steroids and Lipophilic Hormones

智力优势该项目旨在阐明类固醇和甲状腺激素如何与大脑中主要抑制性神经递质γ-氨基丁酸（GABA）的主要受体相互作用。 大脑产生某些类固醇，称为“神经类固醇”，也对甲状腺激素产生反应，它们在化学上相似。 已知这些激素中的每一种都与A型GABA受体（GABA-Ar）相互作用，从而调节GABA对受体的离子通道活性的影响，这一过程在许多大脑过程中表现出显着变化，包括睡眠和焦虑。 然而，受体上这些亲脂性配体结合位点的精确分子机制和位置尚不清楚。 该研究将结合联合收割机的综合计算和实验方法，以研究神经类固醇，甲状腺激素和其他化合物作用于GABA-Ar的分子机制。 特别是，X-射线晶体学表明了抗寄生虫伊维菌素（另一种GABA-Ar调节剂）的可能结合位点。 该项目测试神经类固醇和甲状腺激素是否也与该位点结合：实验方法评估神经类固醇或甲状腺激素与伊维菌素之间结合位点的潜在竞争，而高性能计算方法使用严格的方法来预测神经类固醇或甲状腺激素与GABA-Ar伊维菌素位点相互作用的绝对强度。 为该项目组建的跨学科团队包括具有物理，化学，生物学和高性能计算专业知识的研究人员。 该团队的研究人员对所使用的系统和方法有着丰富的经验，这项工作具有确定GABA受体功能分子基础新细节的前景。更广泛的影响拟议的活动将影响罗格斯-卡姆登社区内的教育和对科学界的贡献，并将为培养具有不同科学背景的学生提供多学科框架。 通过研究和教学的整合，该项目支持的人员将参与指导学生在每年的本科生生物物理学涉及基于物理的生物过程模拟的个人项目。 此外，该项目将提供研究教育的机会，这将加强创新的新的本科和研究生课程，从而丰富国家教育使命以及推进具有全球竞争力的STEM劳动力的发展。 共同PI是NSF STEP项目的负责人，该项目旨在提高STEM学生的定量背景，并在罗格斯-卡姆登校园内创建一个学习社区，并且是NSF REU计算生物学项目的共同PI。 该项目将为来自这些项目的学生提供资源，并提供在实验和计算生物物理学的接口进行研究的机会。

INTELLECTUAL MERITThe project seeks to clarify how steroids and thyroid hormones interact with the main receptor for the primary inhibitory neurotransmitter in the brain, gamma-aminobutyric acid (GABA). The brain produces certain steroids, known as "neurosteroids", and also responds to thyroid hormones, which are chemically similar. Each of these hormones is known to interact with the type A GABA receptor (GABA-Ar), thus modulating the effects of GABA on the ion channel activity of the receptor, a process that exhibits significant changes in numerous brain processes, including sleep and anxiety. However, the precise molecular mechanism and location of these lipophilic ligand binding sites on the receptor are unknown. The research will combine an integrated computational and experimental approach to investigate the molecular mechanism(s) through which neurosteroids, thyroid hormones and other compounds act on GABA-Ar. In particular, X-ray crystallography has suggested a likely binding site for the anti-parasitic ivermectin, another GABA-Ar modulator. This project tests whether neurosteroids and thyroid hormone also bind to this site: the experimental approach evaluates potential competition for binding sites between neurosteroids or thyroid hormone and ivermectin, while the high performance computational approach uses rigorous methods to predict the absolute strength of interactions of neurosteroids or thyroid hormone with the GABA-Ar ivermectin site. The interdisciplinary team assembled for this project includes researchers with expertise in physics, chemistry, biology, and high performance computing. Researchers in the team have extensive experience with the systems and methods to be used, and the work has the prospect to define new details of the molecular basis of GABA receptor function.BROADER IMPACTSThe proposed activities will impact education and contributions to the scientific community within the Rutgers-Camden community, and will provide a multidisciplinary framework for the training of students with different scientific backgrounds. Through an integration of research and teaching, the personnel supported by this project will participate in advising students in a yearly undergraduate biophysics on individual projects involving physics-based simulations of biological processes. In addition the project will provide opportunities for research education that will enhance innovative new undergraduate and graduate programs, thus enriching both national educational mission as well as advancing development of a globally competitive STEM workforce. The Co-PI is director of an NSF STEP project to enhance the quantitative background of STEM students and to create a learning community among them on the Rutgers-Camden campus and is Co-PI on an NSF REU project on computational biology. This project will provide a resource for students from these programs and offer an opportunity to engage in research at the interface of experimental and computational biophysics.