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.

对烟熏烟草及其多种合并症的瘾（从癌症到COPD）有很大的大规模疾病全球影响。尽管我们对影响成瘾的大脑电路有深刻的见解，但我们了解很多关于遗传变异的影响，导致成瘾风险的高水平变异性吸烟及其主要的精神活性剂尼古丁。最初脆弱性的很大一部分青少年和成人中继的烟雾是由于遗传遗传差异所致。响应 NIDA PAR-21-244，该U01专注于发现和理解这些复杂的遗传和分子使用强大的新资源 - 混合大鼠多样性面板（HRDP）的因素。 HRDP是独一无二的综合：1。类似于混合人类种群的遗传多样性非常高； 2 控制和改变药物暴露，并系统地研究基因环境和逐药基因行动； 3。整合遗传，基因组和分子数据的完整定量“上瘾”的方法用于促进精密医学的机械发展。 HRDP由91个不同，完全同生大鼠，近交和F1混合动力车（用于拨号线）：所有人都是“开放访问”，可用于成瘾的研究方面。我们有3个目标：目标1。从青春期开始，我们将收集行为数据使用我们已建立的有限访问操作模型从HRDP静脉内自我管理模型（IVSA），随后是扩展访问模型。通过将这两种模型置，我们效仿有限的初始阶段，青少年期间的发作吸烟以及随后持续的习惯吸烟，这导致尼古丁依赖性。我们的实验设计是性平衡的，交错以最大程度地减少批次效果；我们量化尼古丁的摄入量，尼古丁的动力，戒断严重程度，延长目的地缺乏强化和提示引起的毒品恢复原状； AIM 2。我们生成端粒到telomere （T2T）HRDP关键菌株的基因组组件并构建大鼠pangenome。我们使用测序基于高度准确的太平洋生物科学（PACBIO），为人类T2T组装建立的方法 HIFI长阅读（20KB）和牛津纳米孔（ONT）Ultralong（> 100 kb）数据；目标3。我们将pangenome用于改进的基因分型和QTL映射。人类基因组研究表明，嗜血瘤降低了基因组 “暗物质” - 大大改善了基因分型。我们将为每个尼古丁依赖性行为绘制基因位置，并且相关现象网络并通过与Hu-相比，评估候选基因的转化相关性男人GWAS。结合人类吸烟的大鼠模型，高级长读基因组测序，T2T组件和Pangenomics，我们将准确地定义与与之相关的高影响遗传变异和分子网络尼古丁动机的行为是建模人类吸烟的关键阶段的行为。