Structural Aspects of Oligomerization in the Function of GPCRs

GPCR 功能中寡聚化的结构方面

基本信息

批准号：
8235922
负责人：
Marta Filizola
金额：
$ 12.45万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-15 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8235922
关键词：
Accounting Affect Agonist Amino Acids Applications Grants Binding Bioinformatics Cell membrane Cereals Collaborations Communities Complex Computing Methodologies Cysteine Data Data Sources Databases Development Dimerization Dopamine D2 Receptor Drug abuse Educational process of instructing Electronics Energy Transfer Event Experimental Designs Fluorescence Fostering Funding Future G-Protein-Coupled Receptors GTP-Binding Proteins Goals Heterodimerization Homo Homodimerization Homology Modeling Imagery In Vitro Informatics Information Management Information Systems Knowledge Laboratories Letters Ligand Binding Ligands Link Lipids Maps Mediating Methods Modeling Molecular Molecular Models Mutagenesis Mutate Mutation National Institute of Drug Abuse Online Systems Opioid Receptor Phase Phased Innovation Awards Property Proteins Publications Receptor Activation Reporting Research Research Design Research Personnel Rhodopsin Role Running Scheme Signal Transduction Source Code Specificity Stretching Structure Surface SwissProt System Techniques Testing Therapeutic Agents Time Training United States National Institutes of Health Visit Work base career career development computer studies crosslink data sharing design dimer drug of abuse improved in vivo insight interfacial knowledge base models and simulation molecular modeling molecular recognition monomer mu opioid receptors mutant novel novel strategies receptor receptor function research study simulation success three-dimensional modeling water environment

项目摘要

This KO2 application seeks support from NIDA for Dr. Marta Filizola's continued career development as an independent investigator. Her overall career goal is to contribute to the advancement in knowledge towards a better understanding of the molecular mechanisms underlying G-protein coupled receptor (GPCR)-mediated actions of drugs of abuse by means of computational methodologies that range from bioinformatics to modeling and simulation. In view of the recently established role and importance of GPCR oligomerization in receptor function, current research objectives of the Filizola laboratory are: a) To build refined three-dimensional (3D) models of GPCR oligomers; b) To build activated states of GPCR complexes in the interaction with their G-proteins; c) To study the dynamics of active and inactive GPCR complexes, so as to identify the molecular determinants responsible for allosteric modulation of GPCR function; d) To identify the molecular determinants responsible for the specificity of GPCR oligomerization and functional plasticity; and e) To develop, interpret and disseminate to the scientific community detailed information about the structural context of GPCR oligomerization and its experimentally determined implication for mechanisms of drug abuse. These research objectives are embodied in the proposed aims of the applicant's two currently funded NIDA projects, RO1 DA020032 and R21/R33 DA017976. In pursuit of these long-term research goals, the objectives of the current KO2 application include: 1) freeing the applicant from some teaching and administrative duties to devote nearly full time to develop further her research studies on GPCRs involved in mechanisms of drug abuse; 2) advancingthe applicant's progress in becoming a leader in computational studies of GPCR dimers/oligomers; and 3) intensifying the applicant's training in experimental techniques currently used to study structure, function, and dynamics of GPCR dimers/oligomers. Career development activities proposed in this application include interactions and collaborations designed to expose the applicant to novel computational methodologies as well as molecular and biophysical experimental techniques in vitro and in vivo.

该KO2应用程序为NIDA寻求Marta Filizola博士作为独立调查员的职业发展的支持。她的整体职业目标是为知识的进步做出贡献，以更好地理解G蛋白偶联受体（GPCR）介导的滥用药物的作用，通过计算方法论，从生物信息学到建模和模拟。鉴于GPCR寡聚在受体功能中的最近确定的作用和重要性，Filizola实验室的当前研究目标是：a）构建 GPCR低聚物的精制三维（3D）模型； b）在与G蛋白的相互作用中构建GPCR复合物的活化状态； c）研究主动GPCR复合物的动力学，以确定负责GPCR功能变构调节的分子决定因素； d）确定负责GPCR寡聚和功能可塑性特异性的分子决定因素； e）开发，解释和传播科学界有关GPCR低聚的结构背景及其对药物滥用机制的影响。这些研究目标体现在申请人目前两个资助的NIDA项目RO1 DA020032和R21/R33 DA017976的拟议目的中。为了实现这些长期研究目标，当前KO2申请的目标包括：1）使申请人摆脱一些教学和行政职责，几乎全职全职，以进一步开发有关涉及药物滥用机制的GPCR的研究； 2）促进申请人成为领导者的进步在GPCR二聚体/低聚物的计算研究中； 3）加强申请人在目前用于研究GPCR二聚体/低聚物的结构，功能和动力学的实验技术中的培训。本申请中提出的职业发展活动包括旨在将申请人暴露于新型计算方法以及体外和体内分子和生物物理实验技术的互动和协作。