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.

项目摘要滥用心理刺激剂，包括苯丙胺（AMPHS），是一个重大的公共卫生问题精神病，医学和社会心理并发症。遗传因素对个人的贡献很大对成瘾的敏感性；但是，寻找风险等位基因的成功率有限。这对心理刺激剂的最初敏感性差异很大，并且与持续使用和虐待。可以在动物模型中研究这种特征，这些动物模型已成为研究的强大工具来研究以受控和系统的方式对药物的行为反应。我们的方法组合在此应用中提出的建议将使我们能够利用果蝇遗传学的力量发现新基因以及赋予对AMPH敏感性的基因变体。其快速生命周期和遗传，细胞的可及性和分子分析，苍蝇在更难研究的地区实现了行为研究在脊椎动物模型中。本申请中提供的初步数据表明，飞行的响应通过增加其运动活性并减少睡眠来AMPH。破坏的基因突变多巴胺（DA）合成或多巴胺转运蛋白基因（DAT）功能抑制这些行为反应，证明我们已经开发了一种可靠的行为工具来将遗传变异与表型相关联更改。我们已经制定了一种策略，将这种行为分析与下一代（下一代）相结合测序技术和系统遗传学方法来研究AMPH的遗传结构敏感性并确定影响这种特征的新基因变体。这种集成的方法使得我们与David Goldman博士和神经遗传实验室的Colin Hodgkinson博士的积极合作在NIAAA，最先进的下一代技术，遗传链接研究和功能基因组学专家研究行为特征的方法。我们提出以下特定目的：1）识别基因在野生和之间的底物内和之间的AMPH敏感性差异的变化构成的变体类型，非异生果蝇菌株（CS）。我们将（a）使用选择性育种，并结合使用基因组方法，例如整个基因组测序和缺乏映射，以识别基因变异在不同的CS底物中改变AMPH敏感性，b）使用RNA测序（RNA-Seq）进行轮廓基因表达式变化与不同基质中对AMPH的敏感性的改变相关，2）筛选A 大量的近交菌株识别与对AMPH敏感性改变有关的遗传基因座。我们将（a）筛选果蝇遗传参考面板，由203个基因分型近交系组成对AMPH和（b）使用系统遗传学方法的响应，包括定量性状基因座（QTL）分析和极端的QTL映射，以将对AMPH的敏感性与DNA多态性相关联。