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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要尽管慢性阻塞性肺病流行病学和临床表现存在性别差异，但大多数预防性和治疗策略不考虑生物性别。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，以及概念和将性别纳入研究和临床实践的方法论差距。 X染色体的参与 COPD 中的基因尚未得到广泛研究，特别是不完全 X 染色体失活 (XCI)，这会导致性别之间的基因剂量不平衡以及遗传变异的性别特异性效应。差异与性染色体相关的基因变异可能会对男性和女性产生不同的功能影响。我们的假设是 X 染色体基因调控的变异受到不完整 XCI 的影响，并且 X 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 COPD 的发病和异质性。我们将整合来自肺和血液的 X 染色体多组学数据来自三个研究人群（COPDGene、LTRC 和 LTCOPD）的 COPD 病例和对照样本。我们将通过甲基化数量性状位点 (QTL) 分析研究性别偏向的表观遗传调控（目标 1）；性别- 通过表达 QTL 分析进行有偏向的遗传调控（目标 2）；和通过基因进行性别偏见的调控过程监管网络分析（目标 3）。我们的研究将是第一个模拟 XCI 对基因的影响监管网络检查性别差异的监管过程和相关遗传变异的影响慢性阻塞性肺病（COPD）状态影响、肺气肿和肺功能。我们预计我们的网络分析将指出共同作用以性别特异性方式影响生物功能的遗传变异。鉴于基因逃避 XCI 可能因个体和组织而异，并且与疾病易感性有关，我们将在 mQTL、eQTL 和调控网络的背景下检查逃逸基因，并测试之间的变化慢性阻塞性肺病病例和对照。识别疾病中 XCI 模式的变化将有助于深入了解其机制与 COPD 的疾病发展和性别差异有关。这些发现将帮助我们更好地了解COPD性别差异的生物学机制，为未来的功能提供数据诊断和治疗工具的验证和性别意识开发。该 K01 奖将使博士能够洛佩斯-拉莫斯将利用她现有的分子生物学和转录组学技能来学习关于表观遗传学、统计遗传学、肺病学和综合组学分析以及方法改进性别意识建模和统计比较。洛佩斯-拉莫斯博士制定了详细的培训计划并组建了一支具有互补专业知识的指导团队。该 K01 将使拟议的研究成为可能成功完成并将支持洛佩斯-拉莫斯博士发展成为一名独立研究员，综合呼吸组学和网络医学专家。