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

智力研究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的主要受体--伽马氨基丁酸(GABA)相互作用。大脑会产生某些类固醇，也就是所谓的“神经类固醇”，也会对化学上相似的甲状腺激素做出反应。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对受体离子通道活性的影响，这一过程在包括睡眠和焦虑在内的许多大脑过程中都表现出显著的变化。然而，这些亲脂性配体结合位点在受体上的确切分子机制和位置尚不清楚。这项研究将结合计算和实验方法来研究神经类固醇、甲状腺激素和其他化合物作用于GABA-AR的分子机制(S)。特别是，X射线结晶学表明，另一种GABA-Ar调节剂-伊维菌素可能与抗寄生虫伊维菌素结合。本项目测试神经类固醇和甲状腺激素是否也与这个位点结合：实验方法评估神经类固醇或甲状腺激素与伊维菌素结合位点的潜在竞争，而高性能计算方法使用严格的方法预测神经类固醇或甲状腺激素与GABA-AR伊维菌素结合位点的绝对强度。为这个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。团队中的研究人员在将要使用的系统和方法方面拥有丰富的经验，这项工作有望定义GABA受体功能的分子基础的新细节。BROADER IMPACTS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，并将为具有不同科学背景的学生的培训提供一个多学科框架。通过研究和教学的结合，该项目支持的人员将参与每年一次的本科生生物物理学课程，就涉及生物过程的基于物理的模拟的个别项目向学生提供建议。此外，该项目将为研究教育提供机会，加强创新的本科生和研究生课程，从而丰富国家教育使命，促进具有全球竞争力的STEM劳动力的发展。Co-PI是NSF STEP项目的负责人，该项目旨在增强STEM学生的量化背景，并在罗格斯-卡姆登校园内为他们创建一个学习社区，并是NSF REU计算生物学项目的Co-PI。这个项目将为这些项目的学生提供资源，并提供一个在实验和计算生物物理学的界面上从事研究的机会。

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.