Structural Approaches for Understanding Opioid and ??-Receptor Interactions

描述(申请人提供)：阿片类药物仍然是围术期和慢性疼痛治疗的主要药物，但其副作用，包括呼吸抑制、便秘、成瘾和其他，与我们患者的发病率和死亡率有关，并带来重大的经济和政治负担。由于止痛药和副作用都被认为是由MU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会为解决这一临床难题提供线索。我的长期目标是利用生化、生物物理、蛋白质工程和高分辨结构方法来揭示阿片类药物和阿片受体的分子识别机制。在本项目中，提出了4个具体目标。在目标1中，我们将结合视紫红质结构数据和新获得的人β2肾上腺素能受体的实验结构，建立一个新的人类MUR结构模型。这将使阿片类药物和MUR相互作用能够在计算层面上进行研究。在目标2中，我们将设计一种水溶的，但结构不变的水溶Mu受体(WSMUR)的变体，用于在溶液条件下阿片类药物和受体的动态相互作用。在目标3中，我们将表示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的WSMUR。在目标4中，我们将使WSMUR具体化，以便在存在或不存在阿片类药物的情况下进行结构测定。作为一名麻醉师，曾在日本和美国的中国学术中心接受培训，刘医生坚定地致力于学术麻醉事业。他的最终职业目标是更好地了解阿片和阿片受体的相互作用，并利用这些数据开发最佳止痛药，最终提高患者的护理和满意度。这项提议将通过提供进一步的培训和资源来帮助他实现自己的目标。他的合作导师已经建立了培养初级教员的记录。再加上他目前的技能，通过K-08进行的高级培训将帮助刘博士向围手术期医学领域的独立内科科学家过渡。 公共卫生相关性：该项目使用替代的结构方法来调查阿片类药物和人类Mu受体之间的关系。来自该项目的信息可能有助于设计副作用最小的新型阿片类止痛药，改善疼痛控制，并解决与阿片类药物使用和滥用有关的问题。因此，该项目对公共卫生具有重大影响。

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.