Structural Aspects of Oligomerization in the Function of GPCRs

描述（由申请人提供）：候选人的总体研究目标是获得对药物滥用中涉及的G蛋白偶联受体（GPCRs）的结构和动力学的严格的机理性洞察，从而提供通常难以通过实验获得的分子细节水平，但它对改进治疗的合理发现具有直接影响。继她的兴趣整合尖端的计算方法与国家的最先进的，强大的实验方法，以产生受体-受体相互作用的可测试的假设，导致寡聚化在受体功能中的作用的理解，候选人正在寻求一个额外的保护时间接受培训荧光为基础的实验技术和行为研究从一些专家，长期合作者。在强有力的机构承诺的支持下，候选人的具体长期研究目标是：1）进一步促进阿片受体的动态机制，2）开发旨在促进目前对活细胞中GPCR时空组织及其与功能关系的理解的工具，3）充分利用最近可获得的与药物滥用有关的GPCR的高分辨率结构信息，并使用增强的分子动力学（MD）模拟与虚拟筛选方法相结合，功能研究和结构指导的化学合成，以发现新的非经典阿片样物质配体，通过靶向特定的受体构象或寡聚状态，可以开发成更有效的治疗剂或作为化学探针来研究受体动力学和功能。在K 02更新申请的支持下保护时间是必要的，因为a）候选人没有接受过实验生物物理技术或行为研究的正式培训，以及B）候选人有兴趣与她的计算研究相结合的一些最先进的生物物理技术目前处于开发的早期阶段，并且可能需要一些额外的时间来确立它们自身作为实现对细胞膜中GPCR的时空组织以及最终其与功能的关系的突破性机制洞察的手段。参与这一早期开发的机会具有优势，可以通过该领域专家的集中培训将目前对实验的理解提升到更深的层次，这些专家恰好是候选人的长期合作者。总之，在追求她的研究计划的同时，顺便为一些博士后和本科生提供指导，候选人将开发新技能，学习新方法，这将推进她的工作及其潜力，以提高对GPCR功能的结构基础的理解，从而为确立靶向GPCR寡聚体治疗各种神经系统疾病的潜在价值奠定了基础，包括成瘾和其他精神疾病。这是一项非常具有挑战性的工作，通过发现副作用较小的改进药物，对生物医学研究产生重大影响的前景证明了这一点。

DESCRIPTION (provided by applicant): The candidate's overall research goal is to obtain rigorous mechanistic insight into the structure and dynamics of G Protein-Coupled Receptors (GPCRs) involved in drug abuse, thus contributing a level of molecular detail that is often difficult to obtain experimentally, yet it has direct implications on the rational discovery of improved therapeutics. Following her interest in integrating cutting-edge computational methods with state-of-the-art, powerful experimental approaches to generate testable hypotheses of receptor-receptor interactions leading to an understanding of the role of oligomerization in receptor function, the candidate is seeking an additional period of protected time to receive training in fluorescence-based experimental techniques and behavioral studies from a number of expert, long-term collaborators. Supported by strong institutional commitment, the candidate's specific long-term research objectives are: 1) To further contribute to the dynamic mechanisms of opioid receptors, 2) To develop tools aimed at advancing current understanding of the spatio-temporal organization of GPCRs in living cells, and its relation to function, and 3) To take full advantage of the recent high-resolution structural information available for GPCRs involved in drug abuse and use enhanced molecular dynamics (MD) simulations combined with virtual screening methods, functional studies, and structure-guided chemical synthesis, to discover novel, non-classical opioid ligands that, by targeting specific receptor conformations or oligomeric states, can either be developed into more effective therapeutics or serve as chemical probes to study receptor dynamics and function. Protected time under the auspices of a K02 renewal application is necessary because a) the candidate has no formal training in experimental biophysical techniques or behavioral studies, and b) some of the state-of-the-art biophysical techniques the candidate is interested in integrating with her computational studies are currently at the early stage of their development, and may require some extra time to establish themselves as means to achieve breakthrough mechanistic insight into the spatio-temporal organization of GPCRs in the cell membrane, and ultimately, its relation to function. The opportunity to participate in this early development has the advantage to take current understanding of the experiments to a much deeper level through focused training from experts in the field who happen to be long-term collaborators of the candidate. In summary, while pursuing her research plan, and incidentally providing mentorship for a number of postdoctoral and undergraduate students, the candidate will develop new skills and learn new methods that will advance her work and its potential to improve understanding of the structural bases of the functions of GPCRs, thus laying the foundation for establishing the potential value of targeting GPCR oligomers for the treatment of various nervous system disorders, including addiction and other mental illnesses. This is a very challenging undertaking, justified by the prospects of impacting significantly biomedical research through the discovery of improved drugs with lesser side effects.