Structural Aspects of Oligomerization in the Function of GPCRs

描述（由申请人提供）：本K02申请寻求NIDA对Marta Filizola博士作为独立研究者的持续职业发展的支持。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，为更好地理解g蛋白偶联受体（GPCR）介导的药物滥用行为的分子机制的知识进步做出贡献。鉴于近年来GPCR寡聚化在受体功能中的作用和重要性，Filizola实验室目前的研究目标是：a)建立GPCR寡聚物的精细三维（3D）模型；b)构建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GPCR功能变构调节的分子决定因素；d)确定GPCR寡聚和功能可塑性特异性的分子决定因素；e)发展、解释和向科学界传播有关GPCR寡聚化的结构背景及其对药物滥用机制的实验确定含义的详细信息。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。为了实现这些长期的研究目标，目前K02申请的目标包括：1)将申请人从一些教学和管理职责中解放出来，投入几乎全部的时间来进一步开展gpcr参与药物滥用机制的研究；2)推动申请人成为GPCR二聚体/低聚体计算研究的领导者；3)加强对申请人目前用于研究GPCR二聚体/低聚体结构、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，旨在使申请人接触到新颖的计算方法，以及体外和体内的分子和生物物理实验技术。

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.