Sex chromosome gene regulatory networks and COPD

性染色体基因调控网络与慢性阻塞性肺病

• 批准号: 10570379
• 负责人: Camila Lopes-Ramos
• 金额: $ 16.2万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10570379
• 关键词: Accounting; Affect; Age; Alleles; Apoptosis; Award; Awareness; Biological; Biological Process; Blood specimen; Childhood Asthma; Chronic Obstructive Pulmonary Disease; Cilia; Clinical; Communities; Data; Data Analyses; Development; Diagnosis; Diagnostic; Disease; Disease susceptibility; Epidemiology; Epigenetic Process; Extracellular Matrix; Female; Funding; Future; Gene Dosage; Gene Expression; Gene Expression Profiling; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Genetic Variation; Genotype; Genotype-Tissue Expression Project; Goals; Health; Heterogeneity; Incidence; Individual; Inflammation; Investigation; K-Series Research Career Programs; Knowledge; Learning; Leukocytes; Link; Lung; Lung diseases; Medicine; Mentored Research Scientist Development Award; Mentors; Methodology; Methods; Methylation; Modeling; Molecular; Molecular Biology; Morphogenesis; Multiomic Data; Onset of illness; Outcome; Oxidative Stress; Pathogenesis; Pathway Analysis; Pathway interactions; Pattern; Phenotype; Preventive; Process; Pulmonary Emphysema; Pulmonary Fibrosis; Pulmonology; Quantitative Trait Loci; Regulation; Research; Research Personnel; Resources; Sampling; Severities; Severity of illness; Sex Bias; Sex Chromosomes; Sex Differences; Site; Structure of parenchyma of lung; Systems Biology; Testing; Therapeutic; Tissues; Training; Validation; Variant; Whole Blood; Work; X Chromosome; X Inactivation; advanced system; affection; biological sex; clinical practice; cohort; comorbidity; detection method; differential expression; disease heterogeneity; disorder risk; epigenetic regulation; gene regulatory network; genetic variant; genome sequencing; genomic data; insight; male; neglect; precision medicine; programs; pulmonary function; respiratory; sex; sex development disorder; skills; smoking exposure; study population; tool; transcription factor; transcriptomics; treatment response; whole genome; Accounting; Affect; Age; Alleles; Apoptosis; Award; Awareness; Biological; Biological Process; Blood specimen; Childhood Asthma; Chronic Obstructive Pulmonary Disease; Cilia; Clinical; Communities; Data; Data Analyses; Development; Diagnosis; Diagnostic; Disease; Disease susceptibility; Epidemiology; Epigenetic Process; Extracellular Matrix; Female; Funding; Future; Gene Dosage; Gene Expression; Gene Expression Profiling; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Genetic Variation; Genotype; Genotype-Tissue Expression Project; Goals; Health; Heterogeneity; Incidence; Individual; Inflammation; Investigation; K-Series Research Career Programs; Knowledge; Learning; Leukocytes; Link; Lung; Lung diseases; Medicine; Mentored Research Scientist Development Award; Mentors; Methodology; Methods; Methylation; Modeling; Molecular; Molecular Biology; Morphogenesis; Multiomic Data; Onset of illness; Outcome; Oxidative Stress; Pathogenesis; Pathway Analysis; Pathway interactions; Pattern; Phenotype; Preventive; Process; Pulmonary Emphysema; Pulmonary Fibrosis; Pulmonology; Quantitative Trait Loci; Regulation; Research; Research Personnel; Resources; Sampling; Severities; Severity of illness; Sex Bias; Sex Chromosomes; Sex Differences; Site; Structure of parenchyma of lung; Systems Biology; Testing; Therapeutic; Tissues; Training; Validation; Variant; Whole Blood; Work; X Chromosome; X Inactivation; advanced system; affection; biological sex; clinical practice; cohort; comorbidity; detection method; differential expression; disease heterogeneity; disorder risk; epigenetic regulation; gene regulatory network; genetic variant; genome sequencing; genomic data; insight; male; neglect; precision medicine; programs; pulmonary function; respiratory; sex; sex development disorder; skills; smoking exposure; study population; tool; transcription factor; transcriptomics; treatment response; whole genome

PROJECT SUMMARY/ABSTRACT Despite established sex differences in COPD epidemiology and clinical manifestations, most preventive and therapeutic strategies do not take biologic sex into consideration. This is due, in large part, to a lack of understanding of the molecular mechanisms that drive these sex differences, as well as conceptual and methodological gaps in incorporating sex into research and clinical practice. The involvement of X chromosome genes in COPD has not been extensively studied, particularly incomplete X chromosome inactivation (XCI), which causes gene dosage imbalance between sexes and sex-specific effects of genetic variation. Differences related to sex chromosomes may allow genetic variations to have distinct functional effects in males and females. Our hypothesis is that variations in X chromosome gene regulation affected by incomplete XCI, and X chromosome genetic variants can help explain molecular mechanisms associated with sex differences in COPD onset and heterogeneity. We will integrate X chromosome multi-omic data from lung and blood samples from COPD cases and controls from three study populations (COPDGene, LTRC, and LTCOPD). We will study sex-biased epigenetic regulation by methylation Quantitative Trait Loci (QTL) analysis (Aim 1); sex- biased genetic regulation by expression QTL analysis (Aim 2); and sex-biased regulatory processes via gene regulatory network analysis (Aim 3). Our investigation would be the first to model the effect of XCI into gene regulatory networks to examine sex divergent regulatory processes and the effect of genetic variants associated with COPD status affection, emphysema, and lung function. We expect that our network analyses will point to genetic variants that work together to influence biological function in a sex-specific manner. Given that genes that escape XCI can vary across individuals and tissues and have been linked to disease susceptibility, we will examine escape genes in the context of mQTL, eQTL, and regulatory networks, and test for changes between COPD cases and controls. Identifying variations in XCI patterns in disease will give insights into the mechanisms associated with both disease development and sex differences in COPD. These discoveries will help us better understand the biological mechanisms of sex differences in COPD, and provide data for future functional validation, and sex-aware development of diagnostic and therapeutic tools. This K01 award will enable Dr. Lopes-Ramos to build upon her existing molecular biology and transcriptomics-focused skill sets in order to learn about epigenetics, statistical genetics, pulmonology, and integrative omic analysis and methods refinement for sex-aware modeling and statistical comparisons. Dr. Lopes-Ramos has developed a detailed training plan and assembled a mentoring team with complementary expertise. This K01 will allow the proposed research to be completed successfully and will support the development of Dr. Lopes-Ramos into an independent researcher, expert in integrative respiratory omics and network medicine.

项目摘要/摘要 尽管COPD流行病学和临床表现存在性别差异，但最预防性和 治疗策略不考虑生物学性别。这在很大程度上是由于缺乏 了解驱动这些性别差异的分子机制，以及概念上的 将性融入研究和临床实践中的方法论差距。 X染色体的参与 COPD中的基因尚未得到广泛的研究，特别是不完整的X染色体灭活（XCI）， 这会导致性别之间的基因剂量失衡与遗传变异的性别特异性作用。差异 与性染色体相关的可能使遗传变异在男性和女性中具有不同的功能作用。 我们的假设是，受不完整XCI和X影响的X染色体基因调节的变化 染色体遗传变异可以帮助解释与性别差异相关的分子机制 在COPD发作和异质性中。我们将整合来自肺和血液中的X染色体多摩变数据 来自COPD病例的样本和来自三个研究人群的对照（COPDGENE，LTRC和LTCOPD）。我们 将通过甲基化定量性状基因座（QTL）分析研究性偏见的表观遗传调节（AIM 1）；性别- 通过表达QTL分析（AIM 2）进行偏见的遗传调节；和性偏见的调节过程通过基因 监管网络分析（AIM 3）。我们的研究将是第一个建模XCI对基因的影响的研究 监管网络检查性别发散的调节过程和相关遗传变异的影响 具有COPD状态感情，肺气肿和肺功能。我们希望我们的网络分析将指向 遗传变体以性别特异性方式共同影响生物学功能。鉴于该基因 逃脱的XCI可以在个人和组织之间有所不同，并且与疾病的易感性有关，我们将 在MQTL，EQTL和监管网络的背景下检查逃生基因，并测试 COPD案件和控件。识别疾病XCI模式的变化将有助于洞悉机制 与COPD的疾病发展和性别差异有关。这些发现将帮助我们更好 了解COPD中性别差异的生物学机制，并为将来的功能提供数据 验证和性感知的诊断和治疗工具的开发。该K01奖将使博士启用 Lopes-ramos以她现有的分子生物学和以转录为中心的技能为基础，以学习 关于表观遗传学，统计遗传学，肺功学和整合层分析以及改进方法 性别感知的建模和统计比较。 Lopes-Ramos博士已制定了详细的培训计划， 组装了一个具有互补专业知识的指导团队。该K01将允许拟议的研究是 成功完成，将支持Lopes-Ramos博士的发展成独立研究人员， 综合呼吸轨迹和网络医学专家。