Genetic Control of Addiction by Host and Microbiome

项目摘要/摘要 该项目的总体长期目标是了解微生物组和寄主遗传学在 物质使用障碍(SUD)。在我国，严重急性呼吸窘迫综合征是一个重大且持续的公共卫生负担。在……里面 2015年，估计有2080万12岁及以上的美国人患有酒精或其他药物使用障碍，而 约有2710万人报告了过去一个月的非法药物使用情况。SUD具有很高的遗传性。事实上，一个 使用候选基因方法和方法已确定与成瘾有关的基因数量 全球气候变化趋势正在逼近。然而，到目前为止发现的基因只占基因的一小部分。 变种。越来越多的证据表明，肠道微生物群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，其中许多与 上瘾。我们的初步数据表明，微生物群与成瘾性之间存在一定的关系 行为。宿主遗传可以影响肠道微生物群的组成。肠道的遗传性 微生物组从动物和人类的研究中都很明显。在这项拟议的研究中，我们的目标是揭示一种 结合宿主遗传学和微生物组的成瘾的综合遗传学基础。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 使用多样性异种繁殖(DO)样本和表型数据的集合来测试我们的假设 宿主遗传学和肠道微生物群的相互作用推动了药物成瘾。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和肠道微生物组与 与新奇相关的行为。在特定的目标2中，我们将确定控制成瘾的遗传基因座 使用静脉药物自我给药(IVSA)系统暴露可卡因，并识别重叠 微生物组与IVSA行为之间的基因座。微生物组的丰度与 目标1中的新奇相关行为和目标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相结合 转录水平上的成员和代谢途径。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群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.