Sex chromosome gene regulatory networks and COPD

项目总结/摘要 尽管COPD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 在将性别问题纳入研究和临床实践方面存在方法上的差距。X染色体的参与 COPD中的基因尚未得到广泛研究，特别是X染色体不完全失活（XCI）， 这导致性别之间的基因剂量不平衡和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允许遗传变异在男性和女性中具有不同的功能效应。 我们的假设是，X染色体基因调控的变化受不完全XCI的影响，而X 染色体遗传变异有助于解释与性别差异相关的分子机制 在COPD发病和异质性方面。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基因座（QTL）分析研究性别偏见的表观遗传调控（目标1）; 通过表达QTL分析的偏向性遗传调控（目的2）;以及通过基因调控的性别偏向性调控过程 监管网络分析（目标3）。我们的研究将是第一个模拟XCI对基因影响的研究 监管网络，以检查性别差异的监管过程和相关的遗传变异的影响 慢性阻塞性肺疾病状态、肺气肿和肺功能。我们希望我们的网络分析能指出 遗传变异共同作用，以性别特异性方式影响生物功能。鉴于基因 逃避XCI可以在个体和组织之间变化，并与疾病易感性有关，我们将 在mQTL、eQTL和调控网络的背景下检查逃逸基因，并测试 COPD病例和对照。识别疾病中XCI模式的变化将有助于深入了解疾病的机制。 与COPD的疾病发展和性别差异相关。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，为今后功能性研究提供数据。 验证和开发具有性别意识的诊断和治疗工具。K 01奖将使博士。 Lopes-Ramos在她现有的分子生物学和转录组学技能的基础上， 关于表观遗传学，统计遗传学，肺病学，综合组学分析和方法改进， 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， 组建了一个具有互补专长的指导小组。该K 01将允许拟议的研究 成功完成，并将支持洛佩斯·拉莫斯博士发展成为一名独立的研究人员， 综合呼吸组学和网络医学专家。

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.