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: 9769862
• 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/9769862
• 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; 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/总结 过去十年，在识别导致疾病风险的基因变异方面取得了快速进展。然而， 这些变异发挥影响的生物学背景尚不完全清楚。例如，香烟 烟雾是慢性阻塞性肺病（COPD）的主要危险因素；然而，只有一个子集 吸烟者会患上慢性阻塞性肺病，这表明遗传学可能在慢性阻塞性肺病的发病机制中发挥作用。基因组- 广泛关联研究已确定了二十多个与慢性阻塞性肺病（COPD）状态相关的基因位点。然而， 这些单核苷酸多态性（SNP）只能解释少量的表型变异 慢性阻塞性肺病。这表明弱表型效应的许多变体共同作用影响慢性阻塞性肺病 病理学。 肺遗传学家现在面临的挑战之一是了解这些 SNP 如何协同工作 影响生物功能，并确定这些功能发挥重要作用的背景。鉴于 与疾病相关的 SNP 通常不会改变蛋白质编码，这些 SNP 可能会影响细胞表型 通过基因表达的调控。 我们建议开发新的监管网络模型来模拟疾病的集体影响- 跨组织和香烟烟雾等暴露的相关 SNP。然后我们将应用这些方法 更好地了解与 COPD 相关的变异体的特定调节功能。 普拉蒂格博士在物理学、复杂系统和基因组学方面的训练为他完成这项工作做好了充分的准备 研究。然而，统计遗传学、功能基因组学、网络理论和 当他开始在该大学担任教职时，肺生物学将有助于他的科学和专业发展 2018 年夏天，钱宁网络医学部 (CDNM)。结合了正式课程， 通过密集的研讨会和跨学科指导，普拉蒂格博士将获得必要的技能来实现他的目标 目标。 CDNM 和哈佛医学院为该领域的研究和培训提供了绝佳的机会 肺部疾病的系统遗传学，五内内有四家教学医院和两所哈佛学校 块半径。 Platig 博士将通过他的主要导师 Dr. Platig 获得广泛的计算资源。 西尔弗曼和他的共同导师奎肯布什博士。此外，普拉蒂格博士将出席与 肺科医生、统计遗传学家和医生定期获取有关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。