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

了解性别特定疾病驱动因素的网络工具

基本信息

批准号：
10654001
负责人：
DAWN L DEMEO
金额：
$ 53.56万
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：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10654001
关键词：
Affect Aging Alzheimer&apos s Disease Awareness Biological Brain Chronic Obstructive Pulmonary Disease Clinical Colon Complex Computer software DNA Methylation DNA Methylation Regulation Data Development Disease Disease Progression Disease model Dose Ensure Epigenetic Process Exhibits Female Future Gender Gene Expression Gene Expression Regulation Generations Genes Genetic Genomics Goals Growth Health Heart Human Individual Longevity Malignant Neoplasms Malignant neoplasm of lung Maps Methods Methylation Mining Modeling Nature Network-based Noise Normal tissue morphology Pathway interactions Pattern Process Regulator Genes Relative Risks Research Risk Scanning Sex Chromosomes Sex Differences Signal Transduction Smoking Behavior Source Code Structure Structure of parenchyma of lung System Therapeutic Therapeutic Intervention Time Tissue Sample Tissues Variant Woman Women&apos s Health Work X Chromosome X Inactivation Y Chromosome disorder risk epigenetic regulation gender difference gene regulatory network genetic association health difference hormone regulation human disease in silico innovation insight male men multiple data types multiple omics network models novel diagnostics open data personalized therapeutic precision medicine response screening sex therapeutic target tool treatment response

项目摘要

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.

抽象的复杂的人类疾病，包括慢性阻塞性肺疾病和许多人类癌症男性和女性之间的巨大差异在风险，疾病进展和对治疗的反应中。我们的以前在男性和女性的正常和疾病时间的工作表明，尽管很少有可以解释观察到的性别的遗传关联或基因表达的显着差异差异，建模基因调节过程可能会导致对性别差异驱动因素的关键见解在健康和疾病中。这表明基于性别的因素和表观遗传变异性可能会一起起作用帮助定义风险和反应。基于性别的差异是不是静态的，而是在个人的寿命中发展，在此期间表观遗传状态和马基因表达的调节可能在与性别相关因素有关。在此应用程序中，我们提出合并DNA甲基化变化，基因调节建模和基于性别调节的螺纹的建议网络评估以更好地了解驱动观察到的性别和与性别相关的差异的因素在人类疾病中。我们在研究计划的背景下设想了三个具体目标，包括：开发用于将性染色体纳入网络模型和方法的工具男性和女性网络；用于设置表观遗传先验和包含的网络工具的完善 DNA甲基化数据作为研究性别知识的性别差异的主要数据；和应用于性别差异的疾病，包括COPD和肺癌作为主要例子。我们扩展网络方法以开发工具，以更好地纳入同种体的影响基因调节。这一点尤其重要，因为我们发现了当前的性别标准化方法染色体基因表达会影响观察到的基因调节相互作用。我们将完善工具将表观遗传学调节纳入我们的性别特异性模型，探索DNA甲基化如何捕获影响基因调节网络结构和疾病风险的性别。了解性别和性别 - 在这种监管景观中的相关差异将有助于我们更好地了解人类疾病并突出显示识别性感的治疗靶标的方法。该提案对RFA的目标有很高的反应 OD-19-029：性别和性别对健康和疾病的影响，因为它将研究基于系统/网络研究性别和性别影响人类疾病的方法以及提供公开可用的工具和网络来促进性别和性别研究。