Structural Aspects of Oligomerization in the Function of GPCRs

这份KO2申请寻求NIDA的支持，以支持Marta Filizola博士作为一名独立调查员的持续职业发展。她的整个职业目标是促进知识的进步，通过从生物信息学到建模和模拟的计算方法，更好地理解G蛋白偶联受体(GPCR)介导的药物滥用作用的分子机制。鉴于最近确立的GPCR寡聚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 目的：建立GPCR寡聚体的精细三维(3D)模型；b)建立GPCR型寡聚体与其G蛋白相互作用的激活状态；c)研究活性和非活性GPCR型复合体的动力学，以确定导致GPCR型功能变构调节的分子决定因素；d)确定GPCR型寡聚化的特异性和功能可塑性的分子决定因素；以及(E)开发、解释和向科学界传播有关GPCR型寡聚的结构背景及其在药物滥用机制中实验确定的含义的详细信息。这些研究目标体现在申请人目前资助的两个NIDA项目--RO1 DA020032和R21/R33 DA017976的拟议目标中。为了追求这些长期的研究目标，目前KO2申请的目标包括：1)将申请者从一些教学和行政职责中解放出来，将几乎全部的时间用于进一步发展她对涉及药物滥用机制的GPCRs的研究；2)促进申请者成为领导者的进步 在GPCR二聚体/低聚体的计算研究中；以及3)加强申请者对目前用于研究GPCR二聚体/低聚体的结构、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旨在使申请者接触新的计算方法以及体外和体内的分子和生物物理实验技术的互动和合作。

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.