Structural Aspects of Oligomerization in the Function of GPCRs

描述(申请人提供)：候选人的总体研究目标是对药物滥用中涉及的G蛋白偶联受体(GPCRs)的结构和动力学获得严格的机械洞察力，从而提供通常难以通过实验获得的分子细节水平，但它对改进疗法的理性发现有直接影响。由于她对将尖端计算方法与最先进的、强大的实验方法相结合，以生成受体-受体相互作用的可测试假说，从而了解寡聚在受体功能中的作用感兴趣，她正在寻求额外的保护期，以接受一些专家的长期合作者提供的基于荧光的实验技术和行为研究方面的培训。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)开发工具，旨在促进当前对活细胞中GPCRs的时空组织及其与功能的关系的了解，以及3)充分利用与药物滥用有关的GPCRs的最新高分辨率结构信息，并使用增强分子动力学(MD)模拟与虚拟筛选方法、功能研究和结构引导的化学合成相结合，以发现新的、非经典的阿片配体，通过针对特定受体构象或低聚体状态，可以被开发成更有效的治疗方法，或者作为化学探针来研究受体的动力学和功能。在K02续展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，以及b)候选人有兴趣结合她的计算研究的一些最先进的生物物理技术目前处于开发的早期阶段，可能需要一些额外的时间来建立自己的手段，以实现突破性的机械性洞察细胞膜中GPCRs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具有优势，可以通过来自该领域专家的集中培训，将目前对实验的理解提高到更深的水平，这些专家恰好是候选人的长期合作者。总之，在执行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，候选人将发展新的技能和学习新的方法，这将促进她的工作及其提高对GPCRs功能的结构基础的理解的潜力，从而为建立靶向GPCR寡聚体治疗各种神经系统疾病(包括成瘾和其他精神疾病)的潜在价值奠定基础。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.