Post-translational Regulation of Opioid Receptors

描述(由申请人提供)：候选人拉克希米·德维博士是西奈山医学院药理系统治疗学系的教授。她目前由两项独立赠款资助：美国国家开发协会/美国国立卫生研究院提供的08863美元--用于研究阿片受体的翻译后调节；以及国家创新和发展研究所/国家卫生研究院提供的26880美元--用于研究神经肽生物合成的调节。候选人的长期职业目标是探索阿片受体特性对药物成瘾形成的贡献，并确定参与这一过程的分子和途径，目的是开发有助于预防和/或治疗药物滥用的药理学工具。西奈山医学院为实现这一目标所必需的协同和协作互动提供了智力环境。高级科学家研究和导师奖将通过减轻相当多的教学和行政职责来促进这一点。德维博士实验室的研究重点一直是探索调节阿片受体功能的分子机制。阿片受体的活性受多种机制的调节。例如，活性在受体本身的水平上以及在内源性多肽(激活受体的)水平上被调节。近年来，这位候选人的研究主要集中在这两种机制上。本申请的研究就是为了进一步探索这两种机制。其具体目的是：(I)研究体内吗啡对5-4受体的信号、成熟和调节；(Ii)研究阿片受体和其他七螺旋受体之间的异源二聚作用；以及(Iii)探索新近发现的非经典加工酶在阿片和其他神经肽水平调节中的生理参与。这项赠款申请中描述的研究将提供关于调节阿片受体功能的早期事件的关键信息。阐明参与受体功能调节的细胞通路是确定适当的药物成瘾药物干预的一个引人注目的策略。该奖项将允许候选人专注于阿片肽及其受体领域的研究。此外，该奖项将帮助指导下一代对探索新机制和确定治疗药物滥用障碍的新目标感兴趣的研究人员。 公共卫生相关性：本申请中描述的研究使用经典技术与新工具和最新技术相结合来表征异二聚化在调节受体信号、成熟/上调中的作用，探索体内异二聚化的生理意义，并探索非经典加工酶在阿片肽生成中的作用。这些研究将为干预药物滥用和成瘾开辟新的途径和/或目标。

DESCRIPTION (provided by applicant): The candidate, Dr. Lakshmi Devi is a Professor in the Department of Pharmacology Systems Therapeutics, Mount Sinai School of Medicine. She is currently funded by two independent grants: DA 08863 from NIDA/NIH- to study post-translational regulation of opioid receptors and NS 26880 from NINDS/NIH-to study regulation of neuropeptide biosynthesis. The long-term career goals of the candidate are to explore the contribution of opioid receptor characteristics to development of drug addiction and to identify molecules and pathways involved in this process with the intent of developing pharmacological tools to help in the prevention and/or treatment of drug abuse. Mount Sinai School of Medicine provides the intellectual environment for synergistic and collaborative interactions necessary to achieve this goal. The Senior Scientist Research and Mentorship Award will facilitate this by relieving considerable amount of teaching and administrative duties. The focus of studies in Dr. Devi's laboratory has been to explore molecular mechanisms modulating opioid receptor function. The activity of opioid receptors is modulated by multiple mechanisms. For example, the activity is modulated at the level of the receptors themselves as well as at the level of endogenous peptides (that activate the receptors). In recent years the candidate's research has focused on both these mechanisms. The studies in this application are to further explore these two mechanisms. The specific aims are: (i) to investigate signaling, maturation and regulation of 5-4 receptors by morphine administration in vivo; (ii) to study the role of heterodimerization between opioid receptors and other heptahelical receptors, and (iii) to explore the physiological involvement of recently identified non-classical processing enzymes in the regulation of opioid and other neuropeptide levels. The studies described in this grant application will provide critical information on early events that regulate opioid receptor function. Elucidation of the cellular pathways involved in modulation of receptor function is a compelling strategy for identifying appropriate pharmacological interventions for drug addiction. This Award will allow the candidate to focus on research in the field of opioid peptides and their receptors. In addition, this Award will help mentor the next generation of researchers interested in exploring novel mechanisms and identifying novel targets for the treatment of drug abuse disorders. PUBLIC HEALTH RELEVANCE: The studies described in this application use a combination of classical techniques with novel tools and state-of-the art technology to characterize the role of heterodimerization in modulating receptor signaling, maturation/upregulation, to explore the physiological significance of heterodimerization in vivo and to explore the role of non-classical processing enzymes in the generation of opioid peptides. These studies will open new avenues and/or targets for intervention in drug abuse and addiction.