Delineating the genetic basis of amphetamine sensitivity using a Drosophila behavioral model

使用果蝇行为模型描述安非他明敏感性的遗传基础

基本信息

批准号：
9920454
负责人：
Jonathan A Javitch
金额：
$ 8.94万
依托单位：
NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9920454
关键词：
Acute Addictive Behavior Alleles Amphetamines Animal Model Area Attention Behavior Behavior Disorders Behavioral Behavioral Assay Behavioral Model Biological Assay Brain Breeding Chromosome Mapping Cognitive Collaborations Complement DNA DNA Sequence Alteration Data Dopamine Drosophila genus Drosophila melanogaster Drug Addiction Euphoria Exhibits Exposure to Gene Expression Genes Genetic Genetic Polymorphism Genetic Techniques Genetic Variation Genetic study Genomic approach Genomics Genotype Goals Heritability Heterogeneity Human Hyperactive behavior Inbred Strain Inbreeding Individual Laboratories Life Cycle Stages Link Medical Membrane Molecular Analysis Motor Motor Activity National Institute on Alcohol Abuse and Alcoholism Nature Pathway interactions Pharmaceutical Preparations Phenotype Phosphorylation Phosphotransferases Physical activity Population Population Study Predisposition Public Health Quantitative Trait Loci Resources Rewards Risk Rodent Self Administration Signal Transduction Sleep System Technology Transcript Variant Vertebrates addiction behavior influence behavioral response behavioral study circadian dopamine transporter drug sensitivity experience extracellular fly functional genomics gene function genetic analysis genetic approach genetic architecture genetic association genetic linkage genetic risk factor genetic variant genome sequencing genome-wide high throughput screening insight methamphetamine effect neurogenetics next generation next generation sequencing novel psychosocial psychostimulant response risk variant stimulant abuse success therapeutic development tool trait transcriptome sequencing vesicular monoamine transporter whole genome

项目摘要

Project Summary Abuse of psychostimulants, including amphetamines (AMPHs), is a major public health problem with profound psychiatric, medical and psychosocial complications. Genetic factors contribute substantially to an individual's susceptibility to developing addiction; however, the search for risk alleles has yielded limited success. The initial sensitivity to psychostimulants varies significantly, and has been associated with continued use and abuse. This trait can be studied in animal models, which have emerged as powerful tools to investigate the behavioral response to drugs in a controlled and systematic manner. The combination of approaches we propose in this application will allow us to harness the power of Drosophila genetics to uncover novel genes and gene variants that confer sensitivity to AMPH. With its rapid life cycle and accessibility to genetic, cellular and molecular analyses, the fly has enabled behavioral studies in areas that are far more difficult to investigate in vertebrate animal models. The preliminary data presented in this application show that that flies respond to AMPH by increasing their locomotor activity and decreasing their sleep. Genetic mutations that disrupt dopamine (DA) synthesis or dopamine transporter gene (DAT) function inhibit these behavioral responses, demonstrating that we have developed a robust behavioral tool to associate genetic variations with phenotypic changes. We have developed a strategy combining this behavioral analysis with next-generation (Next-Gen) sequencing technology and systems genetics approaches to investigate the genetic architecture of AMPH sensitivity and identify new gene variants that influence this trait. This integrated approach is made possible by our active collaboration with Dr. David Goldman and Dr. Colin Hodgkinson at the Laboratory of Neurogenetics at NIAAA, experts in state-of-the-art Next-Gen technologies, genetic linkage studies and functional genomics approaches to the study of behavioral traits. We propose the following specific aims: 1) To identify gene variants that underlie wide variation in AMPH sensitivity within and between substrains of the wild- type, non-isogenic Drosophila strain Canton S (CS). We will (a) use selective breeding, combined with genomic approaches such as whole genome sequencing and deficiency mapping, to identify gene variants that alter AMPH sensitivity in different CS substrains and b) use RNA-sequencing (RNA-seq) to profile gene expression changes associated with altered sensitivity to AMPH in the different substrains and 2) To screen a large population of inbred strains to identify genetic loci associated with altered sensitivity to AMPH. We will (a) screen the Drosophila Genetic Reference Panel, which consists of 203 genotyped inbred lines, for response to AMPH and (b) use systems genetics approaches, including quantitative trait locus (QTL) analysis and extreme QTL mapping, to associate phenotypic variation in sensitivity to AMPH with DNA polymorphisms.

项目概要滥用精神兴奋剂，包括安非他明（AMPH），是一个重大的公共卫生问题，具有深远的影响精神、医学和心理社会并发症。遗传因素对个体的影响很大容易上瘾；然而，寻找风险等位基因的成功有限。这对精神兴奋剂的初始敏感性差异很大，并且与持续使用和虐待。这种特征可以在动物模型中进行研究，动物模型已成为研究以受控和系统的方式对药物产生行为反应。我们的方法组合在这个应用程序中提出的建议将使我们能够利用果蝇遗传学的力量来发现新的基因以及赋予 AMPH 敏感性的基因变异。凭借其快速的生命周期和遗传、细胞的可及性和分子分析，苍蝇使得在更难调查的领域进行行为研究成为可能在脊椎动物模型中。本申请中提供的初步数据表明，苍蝇对 AMPH 通过增加他们的运动活动和减少他们的睡眠来实现。破坏的基因突变多巴胺（DA）合成或多巴胺转运基因（DAT）功能抑制这些行为反应，证明我们已经开发了一种强大的行为工具将遗传变异与表型联系起来变化。我们制定了一种将这种行为分析与下一代（Next-Gen）相结合的策略测序技术和系统遗传学方法研究 AMPH 的遗传结构敏感性并识别影响该性状的新基因变异。这种综合方法的实现是通过我们与神经遗传学实验室的 David Goldman 博士和 Colin Hodgkinson 博士积极合作 NIAAA 拥有最先进的下一代技术、遗传连锁研究和功能基因组学专家行为特征的研究方法。我们提出以下具体目标：1）识别基因野生亚种内部和亚种之间 AMPH 敏感性存在巨大差异的变异型，非等基因果蝇菌株 Canton S (CS)。我们将 (a) 采用选择性育种，并结合基因组方法，例如全基因组测序和缺陷图谱，以识别基因变异改变不同 CS 亚株中的 AMPH 敏感性，b) 使用 RNA 测序 (RNA-seq) 来分析基因不同亚株中与 AMPH 敏感性改变相关的表达变化，以及 2) 筛选大量近交菌株来识别与 AMPH 敏感性改变相关的遗传位点。我们将 (a) 筛选果蝇遗传参考组，该组由 203 个基因型自交系组成，对 AMPH 的反应以及 (b) 使用系统遗传学方法，包括数量性状基因座 (QTL) 分析以及极端的 QTL 定位，将 AMPH 敏感性的表型变异与 DNA 多态性联系起来。