AMP-activated protein kinase (AMPK) and nicotine dependence

AMP 激活蛋白激酶 (AMPK) 和尼古丁依赖性

• 批准号: 9441755
• 负责人: Julie A Blendy
• 金额: $ 35.64万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9441755
• 关键词: 5' -AMP-activated protein kinase; Ablation; Abstinence; Addictive Behavior; Adult; Affinity Chromatography; Anxiety; Attention; Behavior; Behavioral; Binding; Biological Assay; Brain; Brain region; CREB1 gene; Cause of Death; Cessation of life; Chronic; Cognitive deficits; Corpus striatum structure; Data; Development; Disease; Exposure to; FDA approved; Genes; Genetic; Genetic Transcription; Genomic approach; High-Throughput Nucleotide Sequencing; Hippocampus (Brain); Laboratories; Mediating; Mediator of activation protein; Metabolic; Metformin; Molecular; Molecular Target; Mus; Neurons; Nicotine; Nicotine Dependence; Nicotine Withdrawal; Nucleus Accumbens; Outcome; Partner in relationship; Pathway interactions; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacology; Phenotype; Property; Protein Kinase; Protein-Serine-Threonine Kinases; Proteins; Public Health; Relapse; Rewards; Ribosomes; Role; STK11 gene; Saline; Signal Pathway; Signal Transduction; Smoke; Smoker; Smoking; Time; Tobacco smoking behavior; Tobacco use; Transcript; Translations; United States; Virus; Withdrawal; Withdrawal Symptom; associated symptom; chromatin immunoprecipitation; cognitive task; cohort; experimental study; functional genomics; gain of function; nicotine exposure; nicotine use; novel; preference; prevent; preventable death; public health relevance; sensor; smoking cessation; theories; therapy design; transcription factor; translational study; virtual

 DESCRIPTION (provided by applicant): Smoking is the largest preventable cause of death and disease in the United States, with about 46 million U.S. adults currently smoking. Though there are medications approved by the FDA to treat nicotine addiction, they are minimally effective and at least 80% of those seeking treatment relapse within one year. Rewarding aspects of nicotine as well as aversive properties, such as those associated with abstinence, may act synergistically to direct the behavior of smokers toward tobacco consumption. Symptoms associated with nicotine withdrawal include increased anxiety and cognitive deficits. To date, few studies have investigated the molecular and cellular changes that occur during chronic exposure to nicotine and how these molecules are altered during withdrawal. Previously, we and others have established that the transcription factor CREB is a central mediator of addictive behaviors. We now made the discovery that one of the targets of CREB in the brain is the LKB1/AMPK pathway. AMP-activated kinase (AMPK) is an evolutionarily conserved serine/threonine kinase that has a major role in the periphery in sensing cellular energy status and regulating fuel availability. Its role in the brain is virtually unknown. Preliminary data indicates that the AMPK pathway and its downstream targets are misregulated during nicotine exposure and withdrawal. The proposed mechanistic and translational studies will determine the functional role of this protein on nicotine reward behavior and withdrawal symptoms and will afford the development of novel or repurposed pharmacological treatments designed to promote smoking cessation.

 描述（由申请人提供）：吸烟是美国最大的可预防的死亡和疾病原因，目前约有 4600 万美国成年人吸烟，尽管 FDA 批准了治疗尼古丁成瘾的药物，但它们的效果甚微，而且效果有限。至少 80% 寻求治疗的人会在一年内复发，而尼古丁的奖励性以及与戒烟相关的厌恶性可能会协同作用来指导行为。迄今为止，很少有研究调查了长期接触尼古丁期间发生的分子和细胞变化以及这些分子在戒断期间的情况。已经确定转录因子 CREB ​​是成瘾行为的核心介质，我们现在发现大脑中 CREB ​​的靶标之一是 LKB1/AMPK 通路。进化上保守的丝氨酸/苏氨酸激酶在感知细胞能量状态和调节燃料可用性方面发挥着重要作用，其在大脑中的作用几乎未知。初步数据表明，AMPK 通路及其下游目标在尼古丁暴露和拟议的机制和转化研究将确定这种蛋白质对尼古丁奖赏行为和戒断症状的功能作用，并将开发旨在促进戒烟的新型或重新用途的药物治疗。