Yale/NIDA Neuroproteomics Research Center

描述（由申请人提供）： 我们建议维持并不断改进耶鲁大学医学院的NIDA神经蛋白质组学中心。来自耶鲁大学和其他机构（芝加哥大学、康涅狄格大学、洛克菲勒大学、斯坦福大学，在精神兴奋剂和精神药物的分子作用以及神经生物学的其他基本方面的研究方面有着既定记录的W.M.凯克基金会实验室创建NIDA神经蛋白质组学中心。该中心的主要目标是应用高通量，最先进的蛋白质组学方法来分析神经元蛋白质表达和调节的适应性变化，这些变化发生在对药物滥用的反应中。此外，该中心将为中心成员提供蛋白质组学技术培训，并将应用新的蛋白质组学技术回答与滥用药物行为有关的生物学问题。在Kenneth威廉姆斯博士（中心主任）和安格斯奈恩博士（精神病学共同研究者）的指导下，该中心将包括蛋白质分析和鉴定核心，蛋白质翻译后鉴定和分析核心以及靶向蛋白质组学核心。脂质和生物物理学分析将纳入蛋白质谱核心。最后，蛋白质数据库、生物统计学、生物信息学和高性能计算核心将提供必要的支持，积极利用每个蛋白质组技术核心的价值。 伴随药物成瘾的行为适应被认为是大脑奖赏中心短期和长期适应性变化的结果。因此，暴露于滥用药物调节细胞内信号传导过程，进而导致基因表达、蛋白质翻译和蛋白质翻译后修饰的改变。反复接触滥用药物会导致这些信号系统发生长期稳定的变化，这些信号系统对成瘾大脑的化学和结构变化至关重要。该中心通过其多学科和协作组织，汇集了耶鲁大学的教师和他们的合作者，以获得更深入的了解神经元信号传导过程的机制，以及滥用药物如何改变这些信号传导机制。该中心支持的研究的具体目标将包括分析精神兴奋剂、可卡因和安非他明、尼古丁和鸦片制剂的作用。新开发的方法将应用于蛋白磷酸化和神经元蛋白的其他翻译后修饰的研究，以及涉及滥用药物的作用的神经元蛋白的靶向分析。 公共卫生相关性：滥用药物篡夺和改变神经元之间的通信，导致正常神经元功能所需的蛋白质（“神经蛋白质组”）的表达和活性发生稳定变化。提高我们对滥用药物如何改变神经蛋白质组的基本理解，将为药物成瘾过程提供更深入的了解，从而有助于设计新的治疗策略。

DESCRIPTION (provided by applicant): We propose to maintain and to continuously improve the NIDA Neuroproteomics Center at the Yale University School of Medicine. Faculty members from Yale and other institutions (Univ. Chicago, Univ. Connecticut, Rockefeller Univ., Stanford Univ., Univ. Texas) with established records of research into the molecular actions of psychostimulants and psychotropic drugs, as well as of other basic aspects of neurobiology, will continue to work together with members of the W.M. Keck Foundation Laboratory to create the NIDA Neuroproteomics Center. The main goal of the Center is to apply high-throughput, state-of-the-art proteomic methods to analyze adaptive changes in neuronal protein expression and regulation that occur in response to drugs of abuse. In addition, the Center will provide training in proteomics technologies for members of the Center, and will apply new proteomics technologies to answer biological questions related to the actions of drugs of abuse. Under the direction of Dr. Kenneth Williams (Center Director) and Dr. Angus Nairn (Co-Investigator, Psychiatry) in the Administration Core, the Center will include a Protein Profiling and Identification Core, a Protein Post-translational Identification and Profiling Core, and a Targeted Proteomics Core. Lipid and Biophysics analyses will be included in the Protein Profiling Core. Finally, a Protein Database, Biostatistics, Bioinformatics and a High Performance Computing Core will provide essential support that will positively leverage the value of each of the proteomic technology cores. The behavioral adaptations that accompany drug addiction are believed to result from both short and long-term adaptive changes in brain reward centers. Thus, exposure to drugs of abuse regulates intracellular signaling processes and in turn results in alteration of gene expression, protein translation and post-translational modifications of proteins. Repeated exposure to drugs of abuse leads to long-term, stable alterations in these signaling systems that are critical for the changes in brain chemistry and structure of the addicted brain. The Center, through its multidisciplinary and collaborative organization, brings together Yale faculty and their collaborators to gain a deeper insight into the mechanisms of neuronal signaling processes and into how drugs of abuse alter these signaling mechanisms. Specific goals of the research supported by the Center will include analysis of the actions of the psychostimulants, cocaine and amphetamine, nicotine and opiates. Newly developed methods will be applied to the study of protein phosphorylation and other post-translational modifications of neuronal proteins, as well as to the targeted analysis of neuronal proteins implicated in the actions of drugs of abuse. PUBLIC HEALTH RELEVANCE: Drugs of abuse usurp and modify communication between neurons, resulting in stable changes in the expression and activities of proteins (the "neuroproteome") required for normal neuronal function. Improving our fundamental understanding of how drugs of abuse alter the neuroproteome will provide deeper insight into the process of drug addiction and thus help in the design of new therapeutic strategies.