Pangenomics of nicotine abuse in the hybrid rat diversity panel

混合大鼠多样性小组中尼古丁滥用的泛基因组学

基本信息

批准号：
10582448
负责人：
Hao Chen
金额：
$ 69.3万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10582448
关键词：
Abstinence Address Adolescence Adolescent Adult Age Area Automobile Driving Behavior Behavioral Biological Sciences Brain Candidate Disease Gene Chromosome Mapping Chronic Obstructive Pulmonary Disease Cigarette Complex Cues DNA Darkness Data Dependence Development Disease Distant Dose Drug Exposure Drug Interactions Drug abuse Environment Environmental Risk Factor Etiology Experimental Designs Female Future Genes Genetic Genetic Variation Genetic study Genome Genomics Genotype Health Heritability Human Human Genome Hybrids Inbred Strain Inbreeding Individual Intake Intravenous Investigation Malignant Neoplasms Maps Metadata Methods Modeling Molecular Molecular Genetics Moon Motivation National Institute of Drug Abuse Nicotine Nicotine Dependence Nicotine Withdrawal Outcome Parents Pharmaceutical Preparations Phase Phenotype Play Population Proteomics Psychological reinforcement Psychotropic Drugs Quantitative Trait Loci Rat Strains Rattus Reference Standards Relapse Reporting Resources Risk Role Sampling Self Administration Severities Side Single Nucleotide Polymorphism Smoking Smoking treatment Structure Surgeon System Technology Tobacco smoke Variant Vulnerable Populations Withdrawal addiction advanced system base behavioral phenotyping candidate identification causal model cigarette smoke cigarette smoking cofactor comorbidity contig dark matter data structure early adolescence experience gene network genetic analysis genetic approach genetic architecture genetic information genetic variant genome resource genome sequencing genome wide association study genomic locus human model improved individual variation innovation insertion/deletion mutation insight male metabolomics molecular phenotype motivated behavior nanopore neural neurochemistry nicotine abuse nicotine seeking behavior nicotine self-administration novel pan-genome personalized medicine phenome precision medicine preventable death rat genome reference genome response sex telomere tool trait transcriptomics variant detection

项目摘要

Addiction to smoked tobacco and its many comorbid diseases – from cancer to COPD – have a massive global impact. Although we have deep insights into brain circuits that influence addiction, we understand much less about the genetic variants responsible for the high level of individual variability in the risk for addiction to smoked tobacco and its principal psychoactive agent, nicotine. A large fraction of the vulnerability to initially smoke cigarettes in adolescence and to relapse in adults is due to heritable genetic differences. In response to NIDA PAR-21-244, this U01 is focused on discovering and understanding these complex genetic and molecular factors, using a powerful new resource – the hybrid rat diversity panel (HRDP). The HRDP is unique in that it integrates: 1. A very high level of genetic diversity similar to that of admixed human populations; 2. Ways to control and change drug exposures and to systematically study gene-by-environment and gene-by-drug inter- actions; 3. Ways to integrate a full quantitative "addictome" of genetic, genomic, and molecular data that can be used to promote the mechanistic development of Precision Medicine. The HRDP consists of 91 different, fully isogenic rats, both inbred and F1 hybrids (used for diallel crosses): all are "open access" and available to study facets of addiction. We have 3 aims: Aim 1. Beginning in adolescence, we will collect behavioral data from the HRDP using our established limited access operant model of nicotine intravenous self-administration (IVSA), which will be followed by an extended access model. By juxtaposing these two models, we emulate the initial phase of limited, episodic smoking during adolescence, and the subsequent persistent, habitual smoking, which leads to nicotine dependence. Our experimental design is sex-balanced and interleaved to minimize batch effects; we quantify nicotine intake, motivation for nicotine, withdrawal severity, prolongation of seeking despite lack of reinforcement, and cue-induced reinstatement of drug seeking; Aim 2. We generate telomere-to-telomere (T2T) genome assemblies of key strains of the HRDP and construct a rat pangenome. We use the sequencing methods established for the human T2T assembly, based on the highly accurate Pacific Biosciences (PacBio) HiFi long-read (20kb) and Oxford Nanopore (ONT) ultralong (>100 kb) data; Aim 3. We use the pangenome for improved genotyping and QTL mapping. Human genomic studies have shown that pangenomes reduce genomic "dark matter" – greatly improving genotyping. We will map gene loci for each nicotine-dependent behavior and associated phenome networks and evaluate the translational relevance of candidate genes by comparison to hu- man GWAS. Combining rat models of human smoking, advanced long read genome sequencing, T2T assemblies and pangenomics, we will accurately define high impact genetic variants and molecular networks associated with nicotine motivated behavior that models the key stages of human smoking.

吸烟成瘾及其许多合并症（从癌症到慢性阻塞性肺病）对人类造成巨大影响尽管我们对影响成瘾的大脑回路有深入的了解，但我们了解的还很多。较少关注导致成瘾风险高水平个体差异的遗传变异吸食的烟草及其主要精神活性物质尼古丁最初很容易受到影响。青春期吸烟和成年后复发是由于遗传性基因差异造成的。 NIDA PAR-21-244，这个U01专注于发现和理解这些复杂的遗传和分子 HRDP 的独特之处在于它使用了强大的新资源——混合大鼠多样性小组 (HRDP)。整合： 1. 与混合人群相似的非常高水平的遗传多样性； 2. 控制和改变药物暴露并系统地研究基因与环境以及基因与药物之间的相互作用 3. 整合遗传、基因组和分子数据的完整定量“成瘾者”的方法 HRDP 包括 91 个不同的、完全同基因大鼠，近交和 F1 杂交（用于双列杂交）：所有都是“开放获取”并且可供我们有 3 个研究目标：目标 1. 从青春期开始，我们将收集行为数据。来自 HRDP，使用我们建立的尼古丁静脉注射自我给药的有限访问操作模型（IVSA），随后将是扩展访问模型，通过并列这两个模型，我们模拟了青春期期间有限的、偶尔吸烟的初始阶段，以及随后的持续、习惯性吸烟，这会导致尼古丁依赖，我们的实验设计是性别平衡和交错的，以尽量减少批次。影响；我们量化尼古丁摄入量、尼古丁动机、戒断严重程度、寻求尼古丁的时间延长缺乏强化，以及线索诱导的药物寻求恢复；目标 2：我们生成端粒到端粒； (T2T) HRDP 关键菌株的基因组组装并构建大鼠泛基因组我们使用测序。基于高精度 Pacific Biosciences (PacBio) 建立的人类 T2T 组装方法 HiFi 长读长（20kb）和 Oxford Nanopore（ONT）超长（>100 kb）数据；目标 3。我们使用泛基因组改进的基因分型和 QTL 作图人类基因组研究表明，泛基因组减少了基因组。 “暗物质”——极大地改善基因分型，我们将绘制每种尼古丁依赖性行为的基因位点图谱。相关的表型网络并通过与 hu- 比较来评估候选基因的翻译相关性人类 GWAS 结合了人类吸烟的大鼠模型、先进的长读基因组测序、T2T 组装。和泛基因组学，我们将准确定义与相关的高影响遗传变异和分子网络尼古丁驱动的行为模拟了人类吸烟的关键阶段。