Structural Modeling of Brain Sodium and Calcium Channels

脑钠通道和钙通道的结构建模

• 批准号: 6871302
• 负责人: VLADIMIR M YAROV-YAROVOY
• 金额: $ 10.85万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6871302
• 关键词: Xenopus; Xenopus oocyte; calcium channel; computer system design /evaluation; electrophysiology; model design /development; neurotoxins; phosphorylation; physical model; protein structure; second messengers; site directed mutagenesis; sodium channel; structural biology; three dimensional imaging /topography; voltage gated channel

DESCRIPTION (provided by applicant): This proposal is a request for a Mentored Research Scientist Development Award (K01) for senior fellow researcher Dr. Vladimir Yarov-Yarovoy. The candidate holds advanced degrees in Physics (M.S.) and Biochemistry and Molecular Biology (Ph.D.) and is well trained in the field of Neuroscience. The candidate's ultimate goal is to lead an independent research group, which will conduct fundamental research in the field of neuroinformatics - the interdisciplinary field that bridges research in neuroscience with that in informatics. Successful completion of this proposal will further enhance the candidate's expertise in the field of neuroscience and also will allow him to develop the essential theoretical knowledge and experience in the field of informatics. The candidate's long-term research interests include structure function studies of neuronal ion channels and computational modeling of protein structure, protein-protein, and protein-drug interactions. Dr. Yarov-Yarovoy's training will consist of computational biology and computer programming courses and research work under the dual mentorship of Drs. William Catterall and David Baker. Dr. Catterall is an accomplished investigator in studying the structure and function of the brain voltage-gated sodium and calcium channels. Dr. Baker is an accomplished investigator in predicting the three-dimensional protein structure using novel computational methods. The goal of the project is to develop three-dimensional models of the brain voltage-gated sodium and calcium channels. These models will provide key structural information on the molecular basis of the brain sodium and calcium channel gating, their modulation by second messenger-activated protein phosphorylation and by peptide neurotoxins, and their interaction with therapeutically useful pore-blocking drugs. The novel features of the models will be experimentally tested using site-directed mutagenesis and electrophysiological techniques. The novel computational tools developed in this project will be generalized for structure prediction of other ion channels. Finally, understanding the brain sodium and calcium channel function and modulation on the structural level will lead to a better understanding of mechanisms of neuromodulation, which in turn will give us profound insights into the fundamental mechanisms underlying learning, memory, emotion and behavior.

描述（由申请人提供）：本提案是为高级研究员弗拉基米尔亚罗夫-亚罗夫博士申请指导研究科学家发展奖（K 01）。候选人拥有物理学（MS）高级学位。生物化学与分子生物学（博士）在神经科学领域受过良好的训练候选人的最终目标是领导一个独立的研究小组，该小组将在神经信息学领域进行基础研究-跨学科领域，将神经科学研究与信息学研究联系起来。成功完成该提案将进一步提高候选人在神经科学领域的专业知识，并使他能够发展信息学领域的基本理论知识和经验。候选人的长期研究兴趣包括神经元离子通道的结构功能研究和蛋白质结构，蛋白质-蛋白质和蛋白质-药物相互作用的计算建模。 亚罗夫-亚罗夫博士的培训将包括计算生物学和计算机编程课程，以及在威廉卡特拉尔和大卫贝克博士的双重指导下进行的研究工作。卡特拉尔博士是一位在研究脑电压门控钠和钙通道的结构和功能方面卓有成就的研究者。贝克博士是一位成功的研究者，他使用新的计算方法预测蛋白质的三维结构。 该项目的目标是开发脑电压门控钠和钙通道的三维模型。这些模型将提供关键的结构信息的分子基础上的脑钠和钙通道门控，其调制的第二信使活化蛋白磷酸化和肽神经毒素，和它们的相互作用与治疗上有用的孔阻断药物。新功能的模型将进行实验测试，使用定点突变和电生理技术。本计画所发展的新计算工具将推广至其他离子通道的结构预测。最后，了解脑钠和钙通道的功能和结构水平上的调节将导致更好地理解神经调节的机制，这反过来又将使我们深入了解学习，记忆，情绪和行为的基本机制。