Networks Tools to Understand Sex- and Gender-Specific Drivers of Disease

摘要 复杂的人类疾病，包括慢性阻塞性肺病和许多人类癌症， 男性和女性在风险、疾病进展和对治疗的反应方面存在显著差异。我们 以前在男性和女性的正常和疾病组织中的研究表明，尽管很少有 可以解释所观察到的基于性别的遗传关联或基因表达的显著差异 差异，建模基因调控过程可以导致对性别差异的可能驱动因素的关键见解 健康和疾病。这表明基于性别的因素和表观遗传变异可能共同起作用 帮助定义风险和应对措施。这一观察结果得到以下事实的进一步支持： 不是静态的，而是在个体的一生中不断演变，在此期间，表观遗传状态和激素 基因表达调控的改变可能与性别相关因素有关。在本申请中，我们 我建议将DNA甲基化变异、基因调控模型和基于性别的调控机制的思路融合起来， 网络评估，以更好地了解导致观察到的性别差异和与性别有关的差异的因素 在人类疾病中。我们在研究计划中设想了三个具体目标，包括： 开发将性染色体纳入网络模型的工具和比较方法 男性和女性网络;完善网络工具，以确定表观遗传先验和纳入 DNA甲基化数据作为研究性别差异的主要数据; 适用于具有性别差异的疾病，包括COPD和肺癌作为主要示例。我们 扩展网络方法，开发工具，以更好地将异体的影响，在这个过程中， 基因调控这是特别重要的，因为我们已经发现了目前的方法正常化的性别 染色体基因表达可影响观察到的基因调控相互作用。我们将改进工具， 将表观遗传调控纳入我们的性别特异性模型，探索DNA甲基化如何捕获 性别影响基因调控网络结构和疾病风险。了解性-和性别- 这种监管格局的相关差异将有助于我们更好地了解人类疾病， 确定性别意识治疗靶点的方法。这一建议非常符合RFA的目标- OD-19-029：性和性别对健康和疾病的交叉影响，因为它将调查 以系统/网络为基础的方法来调查性别和性别对人类疾病的影响，以及 提供公开可用的工具和网络，以促进性和性别研究。

ABSTRACT Complex human diseases including chronic obstructive pulmonary disease and many human cancers, exhibit strong differences between males and females in risk, disease progression, and response to therapy. Our previous work in normal and disease tissues from males and females has shown that while there are rarely significant differences in genetic associations or gene expression that can explain the observed sex-based differences, modeling gene regulatory processes can lead to key insights into the likely drivers of sex differences in health and disease. This suggests that both sex-based factors and epigenetic variability likely work together to help define risk and response. This observation is further supported by the fact that sex-based differences are not static but rather evolve over the course of an individual’s lifespan, during which epigenetic state and hormonal regulation of gene expression likely change in related to gender-associated factors. In this application, we propose to merge the threads of DNA methylation variation, gene regulatory modeling, and sex-based regulatory network assessments to better understand the factors that drive the observed sex and gender-related differences in human diseases. We envision three specific aims within the context of our research plan, including: Developing tools for the inclusion of sex chromosomes in network models and methods for comparing male and female networks; Refinement of network tools for setting epigenetic priors and inclusion of DNA methylation data as a primary data for studying sex differences informed by gender; and Application to diseases with sex differences, including COPD and lung cancer as primary examples. We expand network methods to develop tools to better incorporate the effects of the allosomes in the process of gene regulation. This is particularly important as we have discovered current methods for normalization of sex chromosome gene expression can influence observed gene regulatory interactions. We will refine tools to incorporate epigenetic regulation into our sex-specific models, exploring how DNA methylation may capture gender to influence gene regulatory network structure and disease risk. Understanding the sex- and gender- related differences in this regulatory landscape will help us better understand human diseases and highlight approaches to identify sex-aware therapeutic targets. This proposal is highly responsive to the goals of RFA- OD-19-029: The Intersection of Sex and Gender Influences on Health and Disease as it will investigate a systems/network based approach to investigating sex and gender influences in human disease, as well as providing publicly available tools and networks to facilitate sex and gender research.