Structural Aspects of Oligomerization in the Function of GPCRs

GPCR 功能中寡聚化的结构方面

• 批准号: 9067291
• 负责人: Marta Filizola
• 金额: $ 12.44万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-15 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9067291
• 关键词: Adverse effects; Award; Biology; Biomedical Research; Career Mobility; Cell membrane; Cells; Chemicals; Collaborations; Computing Methodologies; Development; Drug abuse; Drug usage; Energy Transfer; Female; Fluorescence; Fostering; Foundations; G-Protein-Coupled Receptors; Goals; Grant; Growth; Health; Independent Scientist Award; Knowledge; Lead; Learning Skill; Life; Ligands; Mental disorders; Mentors; Mentorship; Methods; Mission; Molecular; Molecular Conformation; National Institute of Drug Abuse; New York; Opioid; Opioid Receptor; Pharmaceutical Preparations; Play; Publications; Research; Research Methodology; Resolution; Role; Staging; Structure; Structure-Activity Relationship; Students; Techniques; Therapeutic; Time; Training; Work; addiction; base; behavioral study; biophysical techniques; career; career development; chemical synthesis; computer studies; design; flexibility; improved; insight; interest; medical schools; mid-career faculty; molecular dynamics; nervous system disorder; novel; programs; receptor; receptor function; research study; screening; single molecule; tool; undergraduate student; virtual

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.

描述（由申请人提供）：候选人的总体研究目标是获得对涉及药物滥用的 G 蛋白偶联受体 (GPCR) 的结构和动力学的严格机制洞察，从而提供通常难以通过实验获得的分子细节水平，但它对改进疗法的合理发现具有直接影响。由于她有兴趣将尖端计算方法与最先进、强大的实验方法相结合，生成可检验的受体-受体相互作用假设，从而了解寡聚化在受体功能中的作用，该候选人正在寻求额外的一段受保护时间，以接受来自许多专家、长期合作者的基于荧光的实验技术和行为研究的培训。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）进一步为阿片受体的动态机制做出贡献，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，以及 3）充分利用涉及药物滥用的 GPCR 的最新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、功能研究和结构引导化学合成相结合，发现新颖的非经典阿片类配体，通过针对特定受体构象或寡聚状态，可以将其开发为更有效的治疗药物或用作研究受体动力学和功能的化学探针。在 K02 更新申请的支持下，保护时间是必要的，因为 a) 候选人没有接受过实验生物物理技术或行为研究的正式培训，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发展的早期阶段，并且可能需要一些额外的时间来将自己确立为实现对时空组织的突破性机械洞察的手段。 细胞膜中的 GPCR 及其与功能的关系。参与这一早期开发的机会有利于通过该领域专家（恰好是候选人的长期合作者）的集中培训，将当前对实验的理解提升到更深的水平。总之，在执行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，候选人将发展新技能并学习新方法，这将推进她的工作及其提高对 GPCR 功能结构基础的理解的潜力，从而为建立靶向 GPCR 寡聚物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任务，通过发现副作用更小的改进药物，有望对生物医学研究产生重大影响。