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(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批准了一些药物来治疗尼古丁成瘾，但它们的效果很小，寻求治疗的人中至少有80%会在一年内复发。尼古丁的有益方面以及令人厌恶的特性，如与戒烟有关的特性，可能会协同作用，引导吸烟者的行为转向烟草消费。与尼古丁戒断相关的症状包括焦虑增加和认知缺陷。到目前为止，很少有研究调查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过程中是如何变化的。此前，我们和其他人已经证实，转录因子CREB是成瘾行为的中心媒介。我们现在发现，CREB在大脑中的靶点之一是LKB1/AMPK通路。AMP激活的激酶(AMPK)是一种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供应方面发挥重要作用。它在大脑中的作用几乎是未知的。初步数据表明，AMPK通路及其下游靶点在尼古丁暴露和戒断过程中受到错误调控。拟议的机制和翻译研究将确定这种蛋白质在尼古丁奖励行为和戒断症状中的功能作用，并将为开发旨在促进戒烟的新的或改变用途的药物治疗提供支持。