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Integration of Computational and Biological Analysis of Serotonin Transporters

血清素转运蛋白的计算和生物学分析的整合

基本信息

批准号：
7657276
负责人：
Loren Keith Henry
金额：
$ 13.07万
依托单位：
UNIVERSITY OF NORTH DAKOTA
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-01 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7657276
关键词：
Amino Acids Aminobutyric Acids Antidepressive Agents Anxiety Disorders Area Autistic Disorder Binding Binding Sites Biochemical Biochemistry Biological Biology Chemicals Clinical Cocaine Complex Computational Biology Computer Simulation Data Development Disease Docking Dopamine Drosophila genus Drug Delivery Systems Environment Evolution Experimental Models Family Family member Future Genes Glycine Homologous Gene Human Individual Integral Membrane Protein Investigation Ions Laboratories Leucine Ligands Link Major Depressive Disorder Membrane Membrane Proteins Mental Health Mental disorders Methodology Methods Modeling Modification Molecular Mood Disorders Movement Mutagenesis Mutation Nervous system structure Neurologic Neurons Norepinephrine Obsessive-Compulsive Disorder Pattern Pharmaceutical Preparations Pharmacology Play Post-Traumatic Stress Disorders Principal Investigator Process Property Proteins Research Research Personnel Resolution Role Sampling Sequence Alignment Serotonin Side Signal Transduction Stress Structural Models Structure Substrate Specificity Synaptic Vesicles Testing Therapeutic Therapeutic Agents Training Tricyclic Antidepressive Agents Tryptamines Uncertainty United States National Institutes of Health Universities Validation Variant Vertebral column addiction base clinically relevant club drug comparative computer studies depression dopamine transporter drug of abuse ecstasy extracellular inhibitor/antagonist insight instructor knowledge base method development molecular dynamics monoamine mutant neuropsychiatry neurotransmitter release poly(L-glutamic acid(60)-L-alanine(30)-L-tyrosine(10))presynaptic programs protein folding reuptake serotonin transporter small molecule solute symporter uptake

项目摘要

DESCRIPTION (provided by applicant): The purpose of this project is to utilize current experimental data to construct a relevant comparative structural model of the serotonin transporter (SERT) based on a recently crystallized bacterial family member. Recent advancements in computation protein folding have legitimized its use in modeling integral membrane proteins. The principal investigator, who has obtained a strong background in the study of structural aspects of SERT using biochemistry and pharmacology in the laboratory of Dr. Randy Blakely who has an outstanding research record in this area, will pursue training in the area of computational biology with a talented researcher, Dr. Jens Meiler, who has played an intergral role in development of methods to analyze protein-small molecule interaction in silico. This project with its heavy emphasis on computational modeling represents a new direction in research for the P.I. who to date has focused on molecular/biochemical study of membrane proteins. Vanderbilt University offers a superior environment for computational studies through the NIH supported ACCRE processor cluster and multiple genes formally expressed in membrane protein modeling (Lybrand, Chazin). This training will allow Dr. Henry to build, test and refine models of SERT interactions with its substrate serotonin and the club drug MDMA. These studies have the potential to provide significant insight into the structural components necessary for recognition and movement of sertonin and drugs of abuse through the transporter. Furthermore, this training will allow Dr. Henry to apply these methods to future projects and broaden his knowledge base as an academic instructor/investigator. Relevance: The serotonin transporter is arguably the most clinically relevant protein today. It is the major target of antidepressants and several drugs of abuse and has been linked to several psychological disorders including: depression, obsessive-compulsive disorder, post-traumatic stress disorder and more recently to aspects of autism. However, we still do not understand many of the details of how SERT recognizes and moves substrates like serotonin and MDMA into the nerve cell. Understanding these aspects of such an important process in the nervous system could have an important impact on clinical targeting of SERT as well as the related norepinepherine and dopamine transporters all which play critical roles in our neurological and psychological health.

描述（由申请人提供）：该项目的目的是利用当前的实验数据，基于最近结晶的细菌家族成员构建血清素转运蛋白（SERT）的相关比较结构模型。计算蛋白质折叠的最新进展使其在完整膜蛋白建模中的使用合法化。首席研究员在 Randy Blakely 博士的实验室中利用生物化学和药理学研究 SERT 的结构方面获得了强大的背景，Randy Blakely 博士在该领域拥有出色的研究记录，他将与才华横溢的研究员 Jens Meiler 博士一起接受计算生物学领域的培训，Jens Meiler 博士在计算机分析蛋白质-小分子相互作用的方法开发中发挥了重要作用。该项目非常重视计算建模，代表了 P.I. 的研究新方向。迄今为止，谁专注于膜蛋白的分子/生化研究。范德比尔特大学通过 NIH 支持的 ACCRE 处理器集群和在膜蛋白模型中正式表达的多个基因（Lybrand、Chazin）为计算研究提供了优越的环境。该培训将使 Henry 博士能够建立、测试和完善 SERT 与其底物血清素和俱乐部药物 MDMA 相互作用的模型。这些研究有可能对通过转运蛋白识别和移动血清素和滥用药物所需的结构成分提供重要的见解。此外，这次培训将使亨利博士能够将这些方法应用到未来的项目中，并扩大他作为学术讲师/研究员的知识基础。相关性：血清素转运蛋白可以说是当今临床上最相关的蛋白质。它是抗抑郁药和多种滥用药物的主要目标，并与多种心理疾病有关，包括：抑郁症、强迫症、创伤后应激障碍以及最近的自闭症。然而，我们仍然不了解 SERT 如何识别血清素和 MDMA 等底物并将其转移到神经细胞中的许多细节。了解神经系统中这一重要过程的这些方面可能会对 SERT 以及相关的去甲肾上腺素和多巴胺转运蛋白的临床靶向产生重要影响，所有这些都在我们的神经和心理健康中发挥着关键作用。