Genetic Control of Addiction by Host and Microbiome

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在我国造成了重大和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使用障碍， 约有2 710万人报告上个月使用过非法药物。SUD具有高度遗传性。确实 使用候选基因方法已经鉴定出许多基因与成瘾相关， GWAS接近。然而，迄今为止发现的基因只占遗传的一小部分， 变体。越来越多的证据表明，肠道微生物组在行为中起着重要作用。 对可卡因的反应，以及焦虑和抑郁样行为，其中许多是共病的 成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。肠道的遗传性 从动物和人类研究中可以明显看出微生物组。在这项研究中，我们的目标是揭示一个 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 一个项目，收集了多样性远交（DO）样本和表型数据，以检验我们的假设， 宿主遗传学和肠道微生物组的相互作用驱动了药物成瘾。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基因座以及肠道微生物组和 与新奇相关的行为。在具体目标2中，我们将确定控制成瘾的遗传基因座， 可卡因暴露使用静脉药物自我管理（IVSA）系统，并确定重叠 微生物组和IVSA行为之间的基因座。微生物组的丰度与 还将确定目标1中的新奇相关行为和目标2中的IVSA行为。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 成员和代谢途径。总之，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绘药物成瘾的遗传基础。如果我们的 假设得到证实，它可能导致发现一种新的药物成瘾机制，并提供 治疗成瘾的新靶点

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.