Structural Approaches for Understanding Opioid and ??-Receptor Interactions

描述（由申请人提供）：阿片类药物仍然是围手术期和慢性疼痛管理的主要药物，但其副作用（包括呼吸抑制、便秘、成瘾等）与我们患者的发病率和死亡率有关，并造成重大的经济和政治负担。由于镇痛和副作用都被认为是由μ受体（MUR）的激活引起的，因此更好地了解人类MUR的结构和功能关系可能为解决这一临床困境提供线索。我的长期目标是通过生物化学、生物物理学、蛋白质工程和高分辨率结构分析等手段揭示阿片类药物和阿片受体的分子识别机制。在这个项目中，提出了四个具体目标。在目标1中，我们将建立一个新的结构模型，从结合视紫红质的结构数据和新的实验结构的人？2肾上腺素能受体。这将允许在计算水平上进行阿片类药物和MUR相互作用研究。在目标2中，我们将设计一种水溶性但结构不变的水溶性μ受体（WSMUR）的变体，用于在溶液条件下动态阿片样物质和受体相互作用。在目标3中，我们将表达WSMUR用于生物物理表征研究和在溶液条件下与阿片类药物的各种结合研究。在目标4中，我们将在存在或不存在阿片类药物的情况下结晶WSMUR以进行结构测定。作为一名麻醉师，曾在中国，日本和美国的学术中心接受培训，刘医生坚定地致力于学术麻醉的职业生涯。他的最终职业目标是更好地了解阿片类药物和阿片受体的相互作用，并利用这些数据开发最佳镇痛药，最终改善患者护理和满意度。这项建议将通过提供进一步的培训和资源，帮助他实现目标。他的共同导师已经建立了培养初级教师的记录。再加上他目前的技能，通过K-08实现的高级培训将有助于刘医生在围手术期医学领域成为一名独立的医生科学家。 公共卫生相关性：该项目使用替代结构方法来研究阿片类药物与人类μ受体之间的关系。来自该项目的信息可能有助于设计具有最小副作用的新型阿片类镇痛药，改善疼痛控制，并解决与阿片类药物管理和滥用相关的问题。因此，该项目对公共卫生具有重大意义。

DESCRIPTION (provided by applicant): Opioids remain the major medication for perioperative and chronic pain management, but their side effects, which include respiratory depression, constipation, addiction and others, relate to morbidity and mortality in our patients, as well as presenting a significant economic and political burden. Since both the analgesic and side effects are thought to arise from activation of the mu receptor (MUR), a better understanding of the structural and functional relationships of human MUR might provide clues for addressing this clinical dilemma. My long-term goal is to reveal the molecular recognition mechanism of opiates and opiate receptors by using biochemical, biophysical, protein engineering and the high resolution structural approaches. In this project, 4 specific aims are proposed. In aim 1, we will establish a novel structural model of the human MUR from a combination of rhodopsin structural data and the newly available experimental structures of human ?2 adrenergic receptor. This will permit opioid and MUR interaction studies at the computational level. In aim 2, we will engineer a variant of the water soluble, but structurally unaltered water soluble mu receptor (WSMUR) for dynamic opioid and receptor interactions in solution conditions. In aim 3, we will express the WSMUR for biophysical characterization studies and for various binding studies with opioids in solution conditions. In aim 4, we will crystallize the WSMUR for structural determinations in the presence or absence of opioids. As an anesthesiologist, formerly trained in academic centers in China, Japan, and United States, Dr. Liu is firmly committed to a career in academic anesthesia. His ultimate career goal is to achieve a better understanding of opioid and opioid receptor interactions, and use these data to develop optimal analgesics to ultimately improve patient care and satisfaction. This proposal will help him to reach his goals by providing further training and resources. His co-mentors have established records of nurturing junior faculty. Together with his current skill set, the advanced training enabled through the K-08 will help transition Dr. Liu towards an independent physician scientist in the area of perioperative medicine. PUBLIC HEALTH RELEVANCE: This project uses alternative structural approaches to investigate the relationship between opioids and human mu receptor. The information derived from this project may help to design novel opioid analgesics with minimal side effects, improve pain control, and solve issues related to opioids administration and abuse. Thus, this project has significant implications for public health.