权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Assessing the adolescent PFC proteome for mechanisms of escalated alcohol self-administration in adulthood

评估青少年 PFC 蛋白质组以了解成年后自我饮酒升级的机制

基本信息

批准号：
9128400
负责人：
Abigail Elizabeth Agoglia
金额：
$ 3.16万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9128400
关键词：
Adolescence Adolescent Adult Age Alcohol abuse Alcohol consumption Alcohol dependence Alcoholism Alcohols Animals Bioinformatics Brain CNR1 gene Data Development Down-Regulation Ethanol Foundations Goals Immunoblotting Immunohistochemistry Lead Life Measures Medial Mediating Mentors Modification Mus Pattern Phosphorylation Prefrontal Cortex Proteins Proteome Proteomics Recording of previous events Research Research Personnel Research Training Risk Rodent Role Self Administration Signal Pathway Signaling Protein Specificity Staging Sucrose Testing Time Viral Vector Work adolescent alcohol adolescent alcohol exposure adolescent brain development age group age related alcohol effect alcohol reinforcement alcohol response alcohol testing alcohol use disorder alcoholism therapy base cannabinoid receptor cannabinoid receptor interacting protein 1a career critical period design drinking endogenous cannabinoid system experience high throughput screening innovation interest lifetime risk neurobiological mechanism novel novel therapeutic intervention overexpression pre-clinical research public health relevance research study skills treatment group underage drinking

项目摘要

DESCRIPTION (provided by applicant): Adolescence is a critical period during which alcohol drinking increases the risk of lifetime alcohol use disorders (AUDs). However, the neurobiological mechanisms that mediate this increased risk have not been fully identified. To break new ground in our understanding of adolescent vulnerability to AUDs, we propose to conduct a high-throughput screen of the prefrontal cortex (PFC) proteome in mice to identify protein interaction networks that are modified by ethanol in the adolescent and adult mouse brain. These discovery-based experiments will identify novel alcohol-sensitive protein networks in adolescent PFC. Preliminary proteomic findings identified the cannabinoid receptor interacting protein 1a (CRIP1a) as a developmentally regulated ethanol-sensitive protein in the adolescent PFC. Evidence suggests that the endocannabinoid system functionally regulates alcohol drinking in rodents, and significant changes in expression of the cannabinoid receptors occur in the developing brain. Therefore, experiments in this application will also establish a functional role for CRIP1a in adolescent and adult alcohol drinking and determine whether CRIP1a expression mediates the long-term consequences of adolescent alcohol drinking. To determine whether CRIP1a mediates the long-term risk for abuse following adolescent alcohol drinking, we will use viral vector-mediated overexpression of CRIP1a in the adolescent and adult PFC to drive long-term increases in CRIP1a expression and measure operant self-administration of alcohol during adulthood in both age groups. As this manipulation will oppose the effect of ethanol in the adolescent PFC, we expect that it will be protective against enhanced reinforcing effects of alcohol in the adolescent but not adult treatment groups. Together, these experiments will identify novel alcohol sensitive protein-networks in the adolescent PFC and determine if a specific node in these networks, CRIP1a, mediates risk for escalated alcohol self-administration during adulthood after adolescent alcohol exposure.

描述（由申请人提供）：青春期是饮酒增加终生酒精使用障碍（AUD）风险的关键时期。然而，介导这种风险增加的神经生物学机制尚未完全确定。为了在我们对青少年对AUDs的脆弱性的理解中开辟新的天地，我们建议对小鼠的前额叶皮层（PFC）蛋白质组进行高通量筛选，以确定青少年和成年小鼠大脑中被乙醇修饰的蛋白质相互作用网络。这些基于发现的实验将确定青少年PFC中新的酒精敏感蛋白网络。初步的蛋白质组学研究结果确定大麻素受体相互作用蛋白1a（CRIP1a）是青少年PFC中发育调节的乙醇敏感蛋白。证据表明，内源性大麻素系统在功能上调节啮齿动物的饮酒，并且大麻素受体表达的显著变化发生在发育中的大脑中。因此，本申请中的实验还将确定CRIP1a在青少年和成人饮酒中的功能作用，并确定CRIP1a表达是否介导青少年饮酒的长期后果。为了确定CRIP1a是否介导青少年饮酒后的长期滥用风险，我们将在青少年和成人PFC中使用病毒载体介导的CRIP1a过表达来驱动CRIP1a表达的长期增加，并测量两个年龄组成年期间酒精的操作性自我管理。由于这种操作将对抗乙醇在青少年PFC中的作用，我们预计它将在青少年治疗组而不是成人治疗组中保护青少年免受酒精增强作用的影响。总之，这些实验将确定青少年PFC中新的酒精敏感蛋白网络，并确定这些网络中的特定节点CRIP1a是否介导青少年酒精暴露后成年期酒精自我管理升级的风险。