Genetic Control of Addiction by Host and Microbiome

宿主和微生物组对成瘾的遗传控制

• 批准号: 10218130
• 负责人: Jason A Bubier
• 金额: $ 77.76万
• 依托单位: JACKSON LABORATORY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10218130
• 关键词: Addictive Behavior; Affect; Alcohol or Other Drugs use; American; Animals; Antibiotic Therapy; Anxiety; Bacteria; Behavior; Behavioral; Behavioral Genetics; Biological; Brain; Candidate Disease Gene; Cecum; Cocaine; Cocaine Dependence; Collection; Complex; Control Locus; Data; Diet; Disease; Drug Addiction; Drug Use Disorder; Environment; Etiology; Exposure to; Future; Gene Expression; Genes; Genetic; Genetic Transcription; Genetic Variation; Goals; Gold; Heritability; Hippocampus (Brain); Human; Intravenous; Lead; Life Style; Measures; Mediating; Mental Depression; Metabolic Pathway; Metagenomics; Mus; Nature; Pathway interactions; Pharmaceutical Preparations; Phenotype; Play; Property; Public Health; Quantitative Trait Loci; Reporting; Resources; Risk Factors; Role; Sampling; Self Administration; Sleep; Source; Stimulus; Substance Use Disorder; System; Testing; The Jackson Laboratory; Variant; addiction; aged; behavior measurement; behavioral response; cocaine exposure; cocaine self-administration; cohort; comorbidity; experimental study; genetic approach; genetic variant; genome wide association study; genomic locus; gut microbiome; host microbiome; illicit drug use; improved; insight; intravenous drug use; member; microbial; microbiome; microbiome components; microbiome composition; microbiome research; mouse genetics; new therapeutic target; novel; phenotypic data; preference; public health relevance; sex; sleep abnormalities; sleep pattern; therapeutic development; therapy development; transcriptome sequencing

PROJECT SUMMARY/ABSTRACT The overall long-term objective of this project is to understand the role of the microbiome and host genetics in substance use disorders (SUD). SUD presents a significant and ongoing public health burden in our nation. In 2015, an estimated 20.8 million Americans aged 12 or older had alcohol or other drug use disorders, while approximately 27.1 million people reported past-month illicit drug use. SUD are highly heritable. Indeed, a number of genes have been identified as associated with addiction using candidate gene approaches and GWAS approaches. However, genes identified so far only account for a small proportion of the genetic variants. Accumulating evidence suggests that the gut microbiome plays a significant role in behavioral response to cocaine, as well as anxiety- and depression-like behaviors, many of which are comorbid with addiction. Our preliminary data demonstrates that there is a relationship between the microbiome and addictive behavior. Host genetics can influence the composition of the gut microbiome. The heritability of the gut microbiome is evident from both animal and human studies. In this proposed study, we aim to reveal an integrated genetic basis of addiction that combines host genetics and the microbiome. To achieve this goal, we will leverage our expertise in mouse behavioral genetics, the gut microbiome and also leverage an ongoing project with a collection of Diversity Outbred (DO) samples and phenotyping data to test our hypothesis that the interplay of host genetics and the gut microbiome drives drug addiction. In Specific Aim 1, we will identify genetic loci that control the abundance gut microbiome and overlapping loci between the gut microbiome and novelty related behaviors. In Specific Aim 2, we will identify genetic loci that control addiction in the setting of cocaine exposure using the intravenous drug self-administration (IVSA) system, and also identify overlapping loci between the microbiome and IVSA behaviors. The association of abundance of the microbiome with novelty related behaviors in Aim 1 and IVSA behaviors in Aim 2 will also be determined. In Specific Aim 3, we will construct the gene expression network in the brain and gut, and integrate the network with the microbiome members and metabolic pathways at transcription level. Altogether, our proposed project will be the first to delineate the genetic basis of drug addiction by integrating host genetics and the gut microbiome. If our hypothesis is confirmed, it is likely to lead to the discovery of a novel mechanism of drug addiction and provide novel therapeutic targets for addiction.

项目概要/摘要 该项目的总体长期目标是了解微生物组和宿主遗传学在 物质使用障碍（SUD）。 SUD 给我们国家带来了重大且持续的公共卫生负担。在 2015 年，估计有 2080 万 12 岁或以上的美国人患有酒精或其他药物滥用疾病，而 大约 2,710 万人报告了过去一个月的非法药物使用情况。 SUD具有高度遗传性。确实，一个 使用候选基因方法已确定许多基因与成瘾相关，并且 GWAS 逼近。然而，迄今为止发现的基因只占遗传基因的一小部分。 变体。越来越多的证据表明肠道微生物组在行为方面发挥着重要作用 对可卡因的反应，以及类似焦虑和抑郁的行为，其中许多与 瘾。我们的初步数据表明微生物组与成瘾之间存在关系 行为。宿主遗传学可以影响肠道微生物组的组成。肠道的遗传力 动物和人类研究中的微生物组都是显而易见的。在这项拟议的研究中，我们的目标是揭示 成瘾的综合遗传基础，结合了宿主遗传学和微生物组。为了实现这一目标，我们 将利用我们在小鼠行为遗传学、肠道微生物组方面的专业知识，并利用正在进行的 项目收集了多样性远交 (DO) 样本和表型数据来检验我们的假设 宿主遗传学和肠道微生物组的相互作用导致药物成瘾。在具体目标 1 中，我们将确定 控制肠道微生物组丰度的遗传位点以及肠道微生物组和肠道微生物组之间的重叠位点 新奇相关的行为。在具体目标 2 中，我们将确定在以下情况下控制成瘾的基因位点： 使用静脉药物自我给药（IVSA）系统进行可卡因暴露，并识别重叠 微生物组和 IVSA 行为之间的位点。微生物组丰度与 目标 1 中的新颖性相关行为和目标 2 中的 IVSA 行为也将被确定。在具体目标 3 中，我们 将在大脑和肠道中构建基因表达网络，并将该网络与微生物组整合 转录水平的成员和代谢途径。总而言之，我们提出的项目将是第一个 通过整合宿主遗传学和肠道微生物组来描述药物成瘾的遗传基础。如果我们的 假说得到证实，很可能导致药物成瘾新机制的发现，并提供 成瘾的新治疗靶点。