Sex chromosome gene regulatory networks and COPD

项目摘要/摘要 尽管COPD流行病学和临床表现存在明显的性别差异，但大多数预防和治疗 治疗策略不考虑生物性行为。这在很大程度上是由于缺乏 理解驱动这些性别差异的分子机制，以及概念和 将性行为纳入研究和临床实践的方法差距。X染色体的参与 COPD中的基因还没有得到广泛的研究，特别是不完全X染色体失活(XCI)， 这会导致性别间的基因剂量失衡和遗传变异的性别特异性影响。差异 与性有关的染色体可能允许遗传变异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不完全XCI和X的影响 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的发病和异质性方面。我们将整合来自肺和血液的X染色体多组数据 来自三个研究人群(COPDgene、LTRC和LTCOPD)的COPD病例和对照的样本。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)；性别- 通过表达QTL分析进行偏向的遗传调节(目标2)；以及通过基因进行偏向的调节过程 监管网络分析(目标3)。我们的研究将首次将XCI的效应模拟为基因 用于检验性分化调控过程和相关遗传变异影响的调控网络 有COPD状态影响、肺气肿、肺功能。我们预计我们的网络分析将指向 共同作用以性别特有的方式影响生物功能的遗传变异。考虑到这些基因 逃逸XCI可能因个人和组织而异，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 慢性阻塞性肺疾病病例和对照。识别疾病中XCI模式的变异将使人们对其机制有深入的了解 与慢性阻塞性肺疾病的疾病发展和性别差异有关。这些发现将帮助我们更好地 了解慢性阻塞性肺疾病性别差异的生物学机制，为今后的功能研究提供数据 对诊断和治疗工具的验证和性别意识的开发。这一K01奖项将使Dr。 洛佩斯-拉莫斯在她现有的分子生物学和转录组学技能的基础上进行学习 关于表观遗传学、统计遗传学、肺病学以及综合基因组分析和方法的改进 性别感知建模和统计比较。洛佩斯-拉莫斯博士制定了详细的培训计划 组建了一支具有互补专业知识的指导团队。这项K01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独立研究人员， 呼吸系统综合组学和网络医学方面的专家。

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.