The pregnancy transcriptome in rheumatoid arthritis

类风湿性关节炎的妊娠转录组

• 批准号: 10014566
• 负责人: Damini Jawaheer
• 金额: $ 65.16万
• 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/10014566
• 关键词: Adult; Adverse event; Affect; Animal Model; Arthritis; Autoimmune Diseases; Bioinformatics; Biological; Biological Process; Birth; Candidate Disease Gene; Chromatin; Chronic; Data; Denmark; Disease; Environment; Epigenetic Process; Exploratory/Developmental Grant for Diagnostic Cancer Imaging; Exposure to; 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; Registries; Regulation; Reporting; Research Design; Rheumatoid Arthritis; Risk; Role; Sampling; Statistical Data Interpretation; Statistical Methods; Symptoms; Technology; Third Pregnancy Trimester; Toxic effect; Untranslated RNA; Variant; Woman; adverse birth outcomes; arthritis therapy; burden of illness; cohort; disability; epigenetic regulation; genetic signature; healthy pregnancy; improved; innovation; insight; large datasets; men; new therapeutic target; novel; novel marker; novel strategies; novel therapeutics; pregnant; prepregnancy; prospective; recruit; side effect; 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.

项目概要 类风湿性关节炎 (RA) 影响着世界成年人口的 1%，其中包括美国的 150 万成年人，以及 严重加重了全球疾病负担。目前尚无治疗 RA 的方法，并且可以 药物通常与毒性和不良事件的风险相关。然而，众所周知，怀孕 对 RA 具有显着的疾病缓解特性，可导致 50-75% 的患者自然改善， 其机制仍不清楚。我们在此提案中的目标是了解 怀孕期间 RA 自然改善的潜在机制，因此，从长远来看，新的 可以开发治疗方法来模仿怀孕对怀孕之外的 RA 的有益影响， 减轻女性和男性的 RA 症状。我们假设导致的生物过程 妊娠期间 RA 的自然改善反映在妊娠引起的基因变化上 系统层面的表达。我们之前建立了一个独特的 RA 前瞻性妊娠队列 健康女性，在怀孕前、怀孕期间和怀孕后收集样本用于基因表达研究。我们 现在提议检查 RA 和健康女性怀孕期间发生的基因表达变化 该队列的更大样本，以便了解怀孕的潜在机制 自然调节 RA 疾病活动。该提案分为 3 个目标。在目标 1 中，一组候选者 具有与 RA 疾病活动改善相关的表达模式的基因将被 调查了。在目标 2 中，将在怀孕前检查与 RA 相关的基因表达特征，并 将研究妊娠引起的表达变化对 RA 特征的影响。在目标 3 中， 将检查 RA 和健康女性中妊娠诱导的基因表达模式，以深入了解 怀孕期间发生的正常生物学变化，以及这些变化在 RA 中如何改变。在所有 3 个目标中， 将研究可能在怀孕期间调节表达的潜在表观遗传机制 深入了解妊娠期间 RA 的自然改善，以及为什么有些女性不能自然改善 怀孕期间会有所改善，但会恶化。所提出的创新方法包括：a) 独特的前景 怀孕队列，其中包括怀孕前作为基线，b) 成功的招募方法，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 评估基因表达，e) 强大的统计分析方法，以及 f) 表观遗传学研究来检查 候选基因表达的调控。使用所提出的方法进行的此类调查在 正常妊娠和 RA 妊娠的背景。这些发现很有可能导致识别 改进 RA 治疗的新药物靶点，且不会产生现有药物的副作用，以及新的药物靶点 RA 疾病活动的生物标志物。