Context matters: Network modeling of COPD regulatory variants across tissues and exposures

背景很重要：跨组织和暴露的慢性阻塞性肺病监管变异的网络建模

• 批准号: 9983153
• 负责人: John Platig
• 金额: $ 17.24万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9983153
• 关键词: Address; Affect; Area; Automobile Driving; Binding; Biological; Biological Process; Biology; Blood; Cell Line; Cell physiology; Cells; Chromatin; Chronic Obstructive Airway Disease; Code; Communities; Community Networks; Complex; Computing Methodologies; DNase I hypersensitive sites sequencing; Data; Development; Development Plans; Disease; Educational workshop; Elements; Faculty; Feedback; Fibroblasts; Gene Expression; Gene Expression Regulation; Gene Targeting; Genes; Genetic; Genome; Genomics; Genotype; Genotype-Tissue Expression Project; Goals; Immune; Lead; Lung; Lung diseases; Medicine; Mendelian disorder; Mentors; Methods; Modeling; Pathogenesis; Phenotype; Physicians; Physics; Play; Population; Positioning Attribute; Property; Proteins; Quantitative Trait Loci; Radial; Regulation; Research; Research Training; Risk Factors; Role; Schools; Single Nucleotide Polymorphism; Smoker; Smoking; Smoking Status; Structure; Structure of parenchyma of lung; System; Teaching Hospitals; Technology; Testing; Tissues; Training; Untranslated RNA; Variant; Work; career; career development; cell type; cigarette smoke; cohort; computational network modeling; computing resources; disease phenotype; disorder risk; functional genomics; genetic variant; genome wide association study; genomic locus; medical schools; meetings; member; network models; protein function; rare variant; response; skills; theories; trait; transcription factor; transcriptome sequencing; whole genome

Project Abstract/Summary The last decade has seen rapid progress in identifying genetic variants that confer disease risk. However, the biological context in which these variants exert their influence is not fully understood. For example, cigarette smoke is a major risk factor for chronic obstructive pulmonary disease (COPD); however, only a subset of smokers develop COPD, suggesting that genetics may play a role in the pathogenesis of COPD. Genome- wide association studies have identified more than twenty genetic loci associated with COPD status. However, these single nucleotide polymorphisms (SNPs) only explain a small amount of the phenotypic variance of COPD. This suggests that many variants of weak phenotypic effect work together to influence COPD pathobiology. One of the challenges now for pulmonary geneticists is to understand how these many SNPs work together to influence biological function, and to identify the contexts in which those functions are important. Given that disease-associated SNPs often do not alter protein coding, these SNPs likely influence cellular phenotypes through regulatory control of gene expression. We propose to develop new regulatory network models for modeling the collective effect of disease- associated SNPs across tissues and on exposures such as cigarette smoke. We will then apply these methods to better understand the context-specific regulatory function of variants associated with COPD. Dr. Platig’s training in physics, complex systems, and genomics has well prepared him to carry out this research. However, additional training in statistical genetics, functional genomics, network theory, and pulmonary biology will aid in his scientific and professional development as he starts his faculty position at the Channing Division of Network Medicine (CDNM) in the summer of 2018. With a blend of formal coursework, intensive workshops, and interdisciplinary mentoring, Dr. Platig will obtain the necessary skills to achieve his goals. The CDNM and Harvard Medical School provide outstanding opportunities for research and training in the systems genetics of pulmonary disease, with four teaching hospitals and two Harvard schools within a five block radius. Dr. Platig will have access to extensive computing resources through his primary mentor, Dr. Silverman, and through his co-mentor Dr. Quackenbush. In addition, Dr. Platig will attend regular meetings with pulmonologists, statistical geneticists, and physicians to get regular feedback on his research and training. This combination of research and training will prepare Dr. Platig for identifying and tackling the open challenges in the systems genetics of pulmonary disease.

项目摘要/摘要 在过去的十年中，在识别赋予疾病风险的遗传变异方面取得了迅速进展。但 这些变体发挥其影响的生物学背景尚未完全了解。例如，香烟 吸烟是慢性阻塞性肺疾病（COPD）的主要危险因素;然而， 吸烟者发生COPD，表明遗传学可能在COPD的发病机制中起作用。基因组- 广泛的关联研究已经鉴定了二十多个与COPD状态相关的遗传基因座。然而，在这方面， 这些单核苷酸多态性（SNPs）只能解释一小部分表型变异， 慢性阻塞性肺病这表明许多弱表型效应的变体共同作用影响COPD 病理生物学 现在肺遗传学家面临的挑战之一是了解这些SNPs是如何协同工作的 影响生物功能，并确定这些功能重要的背景。鉴于 疾病相关的SNP通常不改变蛋白质编码，这些SNP可能影响细胞表型 通过基因表达的调节控制。 我们建议开发新的调控网络模型，用于模拟疾病的集体效应- 相关的SNP跨组织和暴露，如香烟烟雾。然后我们将应用这些方法 以更好地了解COPD相关变异体的环境特异性调节功能。 普拉蒂格博士在物理学、复杂系统和基因组学方面的训练使他为实现这一目标做好了充分的准备 research.然而，在统计遗传学，功能基因组学，网络理论， 肺生物学将有助于他的科学和专业发展，因为他开始了他的教师职位在 Channing Division of Network Medicine（CDNM），2018年夏天。在正式的课程中， 通过密集的研讨会和跨学科的指导，Platig博士将获得必要的技能，以实现他的目标。 目标. CDNM和哈佛医学院为研究和培训提供了出色的机会， 系统遗传学的肺部疾病，与四个教学医院和两个哈佛学校在五个 街区半径普拉蒂格博士将有机会通过他的主要导师，博士广泛的计算资源。 西尔弗曼，并通过他的共同导师博士Quackenbush。此外，Platig博士还将定期参加与 肺科医生、统计遗传学家和内科医生定期获得关于他的研究和培训的反馈。这 研究和培训的结合将使Platig博士为识别和应对以下领域的开放挑战做好准备： 肺部疾病的系统遗传学