Regulation of Proteasomal Function by Nicotine

尼古丁对蛋白酶体功能的调节

基本信息

批准号：
7361505
负责人：
Mariella De Biasi
金额：
$ 15.35万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-02-01 至 2010-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7361505
关键词：
ATP phosphohydrolase Adaptor Signaling Protein Address Affect Alkaloids Amphetamines Awareness Behavior Behavioral Binding Biochemical Brain Caspase Cell membrane Cells Cessation of life Child Chromosome Pairing DLG4 gene Data Developed Countries Developing Countries Development Drosophila acetylcholine receptor alpha-subunit Enzymes Ethanol Event Exposure to Glutamate Receptor Goals Government Grant Homeostasis In Vitro Individual Infusion procedures Investigation Knock-out Measures Mediating Modeling Molecular Morphine Mus Mutant Strains Mice Nature Neurons Neurotransmitter Receptor Nicotine Nicotine Dependence Nicotinic Receptors Organ Pharmaceutical Preparations Proteasome Binding Proteasome Inhibitor Proteins Regulation Reporting Research Role Saline Scaffolding Protein Smoke Smoker Synapses Synaptic Receptors System Testing Tissues Tobacco Trypsin Ubiquitin Up-Regulation Wild Type Mouse Woman Work World Health Organization chymotrypsin cigarette smoking drug of abuse in vivo inhibitor/antagonist insight interest lipophilicity men mouse model multicatalytic endopeptidase complex neurophysiology novel presynaptic density protein 95 research study scaffold stem synaptic function synthetic peptide

ATP phosphohydrolase Adaptor Signaling Protein Address Affect Alkaloids Amphetamines Awareness Behavior Behavioral Binding Biochemical Brain Caspase Cell membrane Cells Cessation of life Child Chromosome Pairing DLG4 gene Data Developed Countries Developing Countries Development Drosophila acetylcholine receptor alpha-subunit Enzymes Ethanol Event Exposure to Glutamate Receptor Goals Government Grant Homeostasis In Vitro Individual Infusion procedures Investigation Knock-out Measures Mediating Modeling Molecular Morphine Mus Mutant Strains Mice Nature Neurons Neurotransmitter Receptor Nicotine Nicotine Dependence Nicotinic Receptors Organ Pharmaceutical Preparations Proteasome Binding Proteasome Inhibitor Proteins Regulation Reporting Research Role Saline Scaffolding Protein Smoke Smoker Synapses Synaptic Receptors System Testing Tissues Tobacco Trypsin Ubiquitin Up-Regulation Wild Type Mouse Woman Work World Health Organization chymotrypsin cigarette smoking drug of abuse in vivo inhibitor/antagonist insight interest lipophilicity men mouse model multicatalytic endopeptidase complex neurophysiology novel presynaptic density protein 95 research study scaffold stem synaptic function synthetic peptide

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项目摘要

DESCRIPTION (provided by applicant): Over a billion men, women and children worldwide smoke, and tobacco continues to be the largest single cause of premature death in developed countries. Nicotine, the main addictive component of tobacco, produces the neurophysiological, motivational and behavioural changes associated with nicotine addiction. Understanding the neuropharmacological, anatomical and behavioural underpinnings of the psychoactive effects of nicotine is key for the identification of new therapeutical targets and the development of new drugs against nicotine dependence. This proposal stems from recent data in the lab that pinpoint a novel mechanism of action for nicotine. We now show that the drug can change maturation and turnover of scaffolding proteins and neurotransmitter receptors by blocking proteasomal activity. Our data indicate that nicotine's effects on the proteasome occur via both nAChR-mediated and nAChR- independent mechanisms. These results provide a mechanism that could explain some of the effects of nicotine, including the drug-induced changes in protein levels, and nAChR upregulation. This exploratory grant will continue the characterization of the proteasome/nicotine interaction with both in vivo and in vitro mechanisms. To determine whether nicotine's influence on the proteasome is one of the mechanisms underlying the pharmacological effects of nicotine we will examine the behavioral effects of nicotine in mice in which proteasomal function is perturbed by proteasomal inhibitors or the inducible knockout of a proteasomal component. Other biochemical and pharmacological experiments will provide information on the nature of the nicotine/proteasome interaction. The investigation of nicotine's influence on the proteasome is important not only for the effects of nicotine on the brain but it will also provide new insights on the effects of tobacco on tissues and organs that do not express nAChRs.

描述（由申请人提供）：全世界有十亿多人，妇女和儿童，烟草仍然是发达国家过早死亡的最大单一原因。尼古丁是烟草的主要成瘾成分，它会产生与尼古丁成瘾相关的神经生理，动机和行为变化。了解尼古丁的心理活性作用的神经药理学，解剖学和行为基础是鉴定新的治疗靶标和开发针对尼古丁依赖性的新药物的关键。该建议源于实验室中最新数据，该数据指出了尼古丁的新型作用机理。现在，我们表明该药物可以通过阻断蛋白酶体活性来改变脚手架蛋白和神经递质受体的成熟和周转。我们的数据表明，尼古丁对蛋白酶体的影响通过NACHR介导的和NACHR独立机制发生。这些结果提供了一种机制，可以解释尼古丁的某些作用，包括药物诱导的蛋白质水平变化和NACHR上调。该探索性赠款将继续表征蛋白酶体/尼古丁与体内和体外机制的相互作用。为了确定尼古丁对蛋白酶体的影响是尼古丁药理作用的基础机制之一，我们将检查尼古丁在尼古丁在蛋白酶体功能中受到蛋白酶体抑制剂的扰动或蛋白酶体成分诱导的敲除的行为作用。其他生化和药理学实验将提供有关尼古丁/蛋白酶体相互作用性质的信息。对尼古丁对蛋白酶体的影响的研究不仅对尼古丁对大脑的影响很重要，而且还将为烟草对不表达NACHR的组织和器官的影响提供新的见解。