Structural Modeling of Brain Sodium and Calcium Channels

描述(由申请人提供)：本提案是对资深研究员Vladimir Yarov-Yarovoy博士的指导研究科学家发展奖(K01)的请求。应聘者拥有物理学高级学位(M.S.)和生物化学和分子生物学(博士)在神经科学领域训练有素。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-这是一个连接神经科学研究和信息学研究的跨学科领域。成功完成这项提议将进一步提高候选人在神经科学领域的专门知识，并使他能够发展信息学领域的基本理论知识和经验。该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，以及蛋白质结构、蛋白质-蛋白质和蛋白质-药物相互作用的计算建模。 亚罗夫-亚罗沃伊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·卡特罗尔博士和大卫·贝克博士的双重指导下的研究工作。Catterall博士在研究大脑电压门控钠和钙通道的结构和功能方面是一位成就卓著的研究员。贝克博士在使用新的计算方法预测三维蛋白质结构方面是一位成就卓著的研究员。 该项目的目标是开发大脑电压门控钠和钙通道的三维模型。这些模型将提供关于大脑钠和钙通道门控的分子基础、第二信使激活的蛋白磷酸化和多肽神经毒素的调节以及它们与治疗有用的孔道阻断药物的相互作用的关键结构信息。将使用定点突变和电生理技术对模型的新特征进行实验测试。本项目开发的新型计算工具将推广到其他离子通道的结构预测中。最后，在结构水平上了解大脑钠钙通道的功能和调节将有助于更好地理解神经调节的机制，这反过来将使我们对学习、记忆、情绪和行为的基本机制有更深刻的洞察。

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.