The pregnancy transcriptome in rheumatoid arthritis

项目摘要 风湿性关节炎（RA）影响1%的成年世界人口，包括美国的150万成年人，和 对全球疾病负担有很大影响。目前还没有治愈类风湿关节炎的方法， 药物治疗往往伴随着毒性和不良反应的风险。然而，众所周知，怀孕 对RA具有显著的疾病改善特性，在50-75%的患者中诱导自然改善， 其机制仍然未知。我们在本提案中的目标是了解 妊娠期间RA自然改善的潜在机制，因此，从长期来看， 可以开发治疗以模拟妊娠对RA的有益作用， 缓解女性和男性的RA症状。我们假设导致 妊娠期间RA自然改善反映在妊娠诱导的基因变化中 在系统水平上的表达。我们以前建立了一个独特的前瞻性妊娠RA队列， 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，我们建议研究RA和健康女性在怀孕期间基因表达的变化， 该队列的更大样本，以了解妊娠 天然调节RA中的疾病活动。该提案分为三个目标。在目标1中，一组候选 具有与RA疾病活动性改善相关的表达模式的基因将被 研究了在目标2中，将在怀孕前检查与RA相关的基因表达特征， 将研究妊娠诱导的表达变化对RA标记的影响。在目标3中， 妊娠诱导的基因表达模式，在RA和健康妇女将进行检查，以提供深入了解 怀孕期间发生的正常生物学变化，以及这些变化在RA中可能如何改变。在所有三个目标中， 将研究可能在妊娠期间调节表达的潜在表观遗传机制， 提供洞察自然改善类风湿关节炎在怀孕期间，以及为什么有些妇女不 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 妊娠队列，包括妊娠前作为基线，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，和f）表观遗传学研究，以检查 候选基因表达的调控。使用所提出的方法的这种调查是新颖的 正常妊娠和RA妊娠。这些发现很有可能导致识别 用于改善RA治疗而没有当前药物副作用的新型药物靶点， RA疾病活动的生物标志物。

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.