Structural Aspects of Oligomerization in the Function of GPCRs

GPCR 功能中寡聚化的结构方面

• 批准号: 7807205
• 负责人: Marta Filizola
• 金额: $ 12.37万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 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/7807205
• 关键词: Accounting; Affect; Agonist; Amino Acids; Applications Grants; Arts; 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; Homo; 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; Principal Investigator; Progress Reports; 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; Validation; 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; mutant; novel; novel strategies; programs; public health relevance; receptor; receptor function; research study; simulation; success; three-dimensional modeling; water environment

DESCRIPTION (provided by applicant): This K02 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, R01 DA020032 and R21/R33 DA017976. In pursuit of these long-term research goals, the objectives of the current K02 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) advancing the 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. PUBLIC HEALTH RELEVANCE: Understanding of GPCR function has recently been challenged by experimental evidence that several of these receptors are organized in the cell membrane as oligomers with unique pharmacological properties. Oligomeric models of GPCRs resulting from use of computational approaches further supported by experiments are expected to help design more effective and selective agents for therapeutic purposes.

描述（由申请人提供）：本 K02 申请寻求 NIDA 的支持，以支持 Marta Filizola 博士作为独立研究者的持续职业发展。她的总体职业目标是通过从生物信息学到建模和模拟的计算方法，促进知识的进步，更好地理解 G 蛋白偶联受体 (GPCR) 介导的滥用药物作用的分子机制。鉴于最近确定的 GPCR 寡聚化在受体功能中的作用和重要性，Filizola 实验室当前的研究目标是： a) 建立 GPCR 寡聚体的精细三维 (3D) 模型； b) 建立 GPCR 复合物与其 G 蛋白相互作用的激活状态； c) 研究活性和非活性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) 确定导致 GPCR 寡聚化特异性和功能可塑性的分子决定因素； e) 开发、解释并向科学界传播有关 GPCR 寡聚化结构背景及其实验确定的药物滥用机制影响的详细信息。这些研究目标体现在申请人目前资助的两个NIDA项目R01 DA020032和R21/R33 DA017976的拟议目标中。为了实现这些长期研究目标，当前 K02 申请的目标包括： 1) 将申请人从一些教学和行政职责中解放出来，将其投入几乎全部时间来进一步开展与药物滥用机制有关的 GPCR 的研究； 2) 推动申请人成为GPCR二聚体/寡聚体计算研究的领导者； 3) 加强申请人对目前用于研究GPCR二聚体/寡聚体的结构、功能和动力学的实验技术的培训。本申请中提出的职业发展活动包括互动和合作，旨在让申请人接触新颖的计算方法以及体外和体内的分子和生物物理实验技术。 公共健康相关性：对 GPCR 功能的理解最近受到实验证据的挑战，实验证据表明其中一些受体在细胞膜中组织为具有独特药理学特性的寡聚物。由实验进一步支持的计算方法产生的 GPCR 寡聚模型预计将有助于设计用于治疗目的的更有效和选择性的药物。