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G蛋白偶联受体（gpcr）参与药物滥用的结构和动力学的严格机制见解，从而提供通常难以通过实验获得的分子细节水平，但它对合理发现改进的治疗方法具有直接意义。随着她对将尖端计算方法与最先进的强大实验方法相结合的兴趣，产生受体-受体相互作用的可测试假设，从而了解寡聚化在受体功能中的作用，候选人正在寻求额外的保护时间，以接受来自许多专家的基于荧光的实验技术和行为研究的培训，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)进一步研究阿片受体的动态机制；2)开发工具，旨在提高当前对活细胞中gpcr的时空组织及其与功能的关系的理解；3)充分利用最新的高分辨率结构信息，利用增强分子动力学（MD）模拟结合虚拟筛选方法，进行功能研究；结构引导化学合成，发现新的，非经典的阿片配体，通过针对特定的受体构象或寡聚态，可以开发成更有效的治疗方法或作为化学探针来研究受体动力学和功能。在K02更新申请的支持下，保护时间是必要的，因为a)候选人没有在实验生物物理技术或行为研究方面的正式培训，b)候选人有兴趣将一些最先进的生物物理技术与她的计算研究相结合，目前处于发展的早期阶段。并且可能需要一些额外的时间来建立自己作为手段，以实现突破性的机制洞察细胞膜中gpcr的时空组织，并最终了解其与功能的关系。参与这一早期开发的机会有一个好处，即通过该领域的专家（恰巧是候选人的长期合作者）的重点培训，将当前对实验的理解提升到更深的层次。综上所述，在完成她的研究计划，并顺便为一些博士后和本科生提供指导的同时，候选人将发展新的技能和学习新的方法，这将促进她的工作和它的潜力，提高对GPCR功能的结构基础的理解，从而为建立靶向GPCR寡聚物治疗各种神经系统疾病的潜在价值奠定基础。包括上瘾和其他精神疾病。这是一项非常具有挑战性的任务，通过发现副作用较小的改良药物，有望对生物医学研究产生重大影响。

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.