The pregnancy transcriptome in rheumatoid arthritis

项目总结 类风湿性关节炎(RA)影响着世界1%的成年人，包括美国的150万成年人，以及 这大大加重了全球疾病负担。目前还没有治愈类风湿性关节炎的方法，而且 药物往往与毒性和不良事件的风险有关。然而，怀孕是已知的 对类风湿关节炎具有显著的疾病改善性，可使50%-75%的患者自然好转， 其机制(S)尚不清楚。我们在这项建议中的目标是了解 孕期RA自然改善的潜在机制(S)，从长远来看，新的 可以开发治疗方法来模拟怀孕对RA的有益影响， 缓解女性和男性的类风湿性关节炎症状。我们假设生物过程会导致 妊娠期RA的自然改善反映在妊娠诱导的基因变化上 在系统水平上的表达。我们之前建立了一个独特的类风湿性关节炎和 健康妇女，在怀孕前、怀孕期间和怀孕后收集样本进行基因表达研究。我们 现在建议研究RA和健康女性在怀孕期间发生的基因表达变化 这一队列中的更大样本，以了解怀孕的潜在机制(S) 自然调节类风湿性关节炎的疾病活动。该提案分为三个目标。在目标1中，一组候选人 具有与RA疾病活动改善相关的表达模式的基因将是 调查过了。在目标2中，与类风湿性关节炎相关的基因表达特征将在怀孕前和 妊娠诱导的表达变化对RA签名的影响将被调查。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，以提供对 妊娠期间发生的正常生物变化，以及这些变化在类风湿关节炎中可能发生的变化。在所有三个目标中， 可能在怀孕期间调节表达的潜在表观遗传机制将被调查 洞察怀孕期间RA的自然改善，以及为什么有些女性不这样做 在怀孕期间有所改善，但会恶化。拟议的创新方法包括a)独特的前景 怀孕队列，包括以怀孕前为基线，b)成功的招募办法，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 候选基因表达的调控。这类使用拟议方法的调查在 正常妊娠和类风湿性关节炎的情况。这些发现很有可能导致身份识别 新的药物靶点，用于改善RA治疗，而不会出现当前药物的副作用，以及新的 类风湿性关节炎活动性的生物标志物。

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.