The pregnancy transcriptome in rheumatoid arthritis

类风湿性关节炎的妊娠转录组

• 批准号: 9469350
• 负责人: Damini Jawaheer
• 金额: $ 75.18万
• 依托单位: CHILDREN'S HOSPITAL & RES CTR AT OAKLAND
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-20 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9469350
• 关键词: Adult; Adverse effects; Adverse event; Affect; Animal Model; Arthritis; Autoimmune Diseases; Bioinformatics; Biological; Biological Process; Birth; Candidate Disease Gene; Chromatin; Chronic; Data; Data Set; Denmark; Disease; Environment; Epigenetic Process; Exploratory/Developmental Grant for Diagnostic Cancer Imaging; Fetus; Future; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Genes; Goals; Inflammatory; Interferon Type I; Interferons; Investigation; Knowledge; Lead; Literature; Longitudinal Studies; Mediating; Methods; Modeling; Multiple Sclerosis; Outcome; Patients; Pattern; Pharmaceutical Preparations; Population; Pregnancy; Property; Quantitative Trait Loci; Recruitment Activity; Registries; Regulation; Reporting; Research Design; Rheumatoid Arthritis; Risk; Role; Sampling; Statistical Data Interpretation; Statistical Methods; Symptoms; Technology; Toxic effect; Untranslated RNA; Variant; Woman; arthritis therapy; burden of illness; cohort; disability; epigenetic regulation; genetic signature; healthy pregnancy; improved; innovation; insight; men; new therapeutic target; novel; novel marker; novel strategies; novel therapeutics; pregnant; prospective; symptomatic improvement; transcription factor; transcriptome; transcriptome sequencing

PROJECT SUMMARY Rheumatoid arthritis (RA) affects 1% of the adult world population, including 1.5 million adults in the U.S., and contributes significantly to the global burden of disease. There is currently no cure for RA, and available medications are often associated with risks of toxicity and adverse events. However, pregnancy is known to have remarkable disease modifying properties on RA, inducing a natural amelioration in 50-75% of patients, the mechanism(s) of which remain unknown. Our goal in this proposal is to gain an understanding of the mechanism(s) underlying the natural amelioration of RA during pregnancy so that, in the long-term, novel therapy can be developed to mimic the beneficial effect of pregnancy on RA outside the context of pregnancy, to alleviate RA symptoms in both women and men. We hypothesize that the biological processes that lead to the natural improvement of RA during pregnancy are reflected in pregnancy-induced changes in gene expression at the systemic level. We previously established a unique prospective pregnancy cohort of RA and healthy women, with samples collected before, during and after pregnancy for gene expression studies. We now propose to examine changes in gene expression that occur during pregnancy in RA and healthy women in a larger sample of this cohort in order to gain an understanding of potential mechanism(s) whereby pregnancy naturally modulates disease activity in RA. The proposal is divided into 3 aims. In aim 1, a set of candidate genes with expression patterns that are associated with improvement in RA disease activity will be investigated. In aim 2, gene expression signatures associated with RA will be examined before pregnancy and the influence of pregnancy-induced expression changes on the RA signature will be investigated. In aim 3, pregnancy-induced gene expression patterns in RA and healthy women will be examined to provide insight into normal biological changes that occur during pregnancy, and how these may be altered in RA. In all 3 aims, potential epigenetic mechanisms that may be regulating expression during pregnancy will be investigated to provide insight into the natural amelioration of RA during pregnancy, and into why some women do not improve during pregnancy, but worsen. The proposed innovative approach includes a) a unique prospective pregnancy cohort which includes pre-pregnancy as baseline, b) a successful recruitment approach, c) a powerful longitudinal study design, d) state-of-the-art RNA sequencing technology and bioinformatics methods to assess gene expression, e) powerful statistical analysis approaches, and f) epigenetic studies to examine regulation of candidate gene expression. Such investigations using the proposed approach are novel in the context of both normal and RA pregnancies. There is a high potential that the findings can lead to identification of novel drug targets for improved RA therapy without side effects of current medications, and novel biomarkers of RA disease activity.

项目摘要 类风湿关节炎（RA）影响1％的成年世界人口，其中包括美国150万成年人和 为全球疾病负担做出了重大贡献。目前无法治愈RA，可用 药物通常与毒性和不良事件的风险有关。但是，已知怀孕是 具有显着疾病的RA疾病，诱导50-75％的患者自然改善， 其机制仍然未知。我们在此提案中的目标是了解 妊娠期间RA自然改善的基础机制，从长远来看 可以开发治疗以模仿怀孕对怀孕之外的RA的有益作用， 减轻男女的RA症状。我们假设导致的生物过程 怀孕期间RA的自然改善反映在怀孕引起的基因变化中 在系统级别的表达。我们以前建立了RA和RA和 健康妇女，在怀孕之前，期间和之后收集样品进行基因表达研究。我们 现在建议检查RA和健康女性在怀孕期间发生的基因表达变化 该队列的较大样本，以了解怀孕的潜在机制 自然调节RA中的疾病活动。该提议分为3个目标。在AIM 1中，一组候选人 具有与RA疾病活性改善有关的表达模式的基因将是 调查。在AIM 2中，将在怀孕前检查与RA相关的基因表达特征和 将研究怀孕引起的表达变化对RA特征的影响。在AIM 3中， 将检查由RA和健康女性中怀孕引起的基因表达模式 怀孕期间发生的正常生物学变化，以及如何改变RA的生物学变化。在所有三个目标中， 可能会研究可能调节怀孕期间表达表达的潜在表观遗传机制 提供对怀孕期间RA自然改善的见解，以及为什么有些女性不这样做 怀孕期间有所改善，但恶化。拟议的创新方法包括a）独特的潜在 怀孕队列，其中包括孕前为基准，b）成功招募方法，c）a 强大的纵向研究设计，d）最先进的RNA测序技术和生物信息学方法 为了评估基因表达，e）强大的统计分析方法和f）表观遗传学研究 调节候选基因表达。使用拟议方法进行的此类调查在 正常和RA怀孕的背景。这些发现可能导致识别很高的潜力 用于改进RA疗法的新型药物靶标，而没有当前药物的副作用和新颖 RA疾病活动的生物标志物。