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 在识别会议疾病风险的遗传变异方面，最近十年的进步迅速。但是， 这些变体产生其影响的生物学环境尚未完全理解。例如，香烟 烟雾是慢性阻塞性肺疾病（COPD）的主要危险因素；但是，只有一个子集 吸烟者发展COPD，表明遗传学可能在COPD的发病机理中起作用。基因组 广泛的关联研究已经确定了与COPD状态相关的二十多个遗传位置。然而， 这些单一的核苷酸多态性（SNP）仅解释了少量的表型方差 COPD。这表明许多弱表型效应的变体共同影响COPD 病理生物学。 肺遗传学家现在面临的挑战之一是了解这些许多SNP如何一起工作 影响生物学功能，并确定这些功能很重要的环境。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 通过对基因表达的调节控制。 我们建议开发新的监管网络模型，以建模疾病的集体效应 - 将跨组织和诸如香烟烟雾等暴露的SNP相关。然后，我们将应用这些方法 更好地了解与COPD相关的变体的特定上下文调节功能。 Platig博士在物理，复杂系统和基因组学方面的培训已经为他做好了做好的准备 研究。但是，在统计遗传学，功能基因组学，网络理论和 肺部生物学将在他在教职员工职位上的职位上有助于他的科学和专业发展 2018年夏天 密集的研讨会和跨学科指导，Platig博士将获得必要的技能来实现他的 目标。 CDNM和哈佛医学院为研究和培训提供了出色的机会 肺部疾病的系统遗传学，五家教学医院和两所哈佛学校 块半径。 Platig博士将通过其主要导师博士获得广泛的计算资源。 西尔弗曼（Silverman）和他的股东Quackenbush博士。此外，Platig博士将与 肺科医生，统计遗传学家和医生会定期就其研究和培训获得反馈。这 研究和培训的结合将使Platig博士识别和应对公开挑战 肺部疾病的系统遗传学。