Placental Serum Amyloid A as a Therapeutic Target to Prevent Preterm Birth and Prematurity Related Morbidity

摘要 早产(PTB)及其相关的胎儿脑损伤会导致不良的围产儿结局，包括 子女死亡率高，家庭和社会的护理和治疗费用高。病理性免疫 母体炎症(MI)期间胎盘的反应被认为是肺结核和 围产期后遗症。然而，由于胎盘的复杂性，其作用机制尚不清楚。 结构和功能。为此，能够保护人类健康的治疗剂很少。 因接触MI而产生的后代。血清淀粉样蛋白A(SAA)被认为是一种炎性生物标志物， 其病理作用尚未在心肌梗死的背景下进行研究。我们公布的数据表明， SAA2亚型在胎盘发育过程中缺失，但对急性母体感染高度敏感 发炎。在这项提案中，我们计划研究胎盘SAA亚型在响应亚型变化中的作用。 并探讨系统地使用小干扰RNA(SiRNA)抑制Saa2是否缓解 结核病和不良后代后果(目标1)。此外，我们还将比较一下，无论是 通过靶向胎盘输注siRNA给Saa2将比通过 亚慢性母体炎症后系统输液(目标2)。该项目将有重要的 对母胎医学领域的影响，因为它将提供胎盘SAA2作为潜在的治疗靶点 并将展示一种新的靶向将siRNA传递到胎盘的途径，用于治疗MI引起的 肺结核及其相关的胎儿脑损伤。

Summary Preterm birth (PTB) and associated fetal brain injury bring about adverse perinatal outcomes including mortality in offspring, and high cost of care and treatment for the family and society. The pathologic immune responses in the placenta during maternal inflammation (MI) are thought to be the major causes of PTB and perinatal sequelae. Yet, the mechanisms are still not well understood because of the complexity of placental structure and function. Towards that end, there is a paucity of therapeutic agents capable of protecting offspring from exposure to MI. Serum amyloid A (SAA) has been identified as an inflammatory biomarker and its pathologic role has not been studied in the context of MI. Our published data demonstrated that one isoform, SAA2 was absent from the development in the placenta but highly susceptible to acute maternal inflammation. In this proposal, we plan to investigate the role of placental SAA isoforms in response to sub- chronic MI and explore whether inhibition of Saa2 systemically using small interfering RNA (siRNA) alleviates PTB and adverse offspring outcomes (Aim 1). Furthermore, we will compare the effect that whether administration of siRNA to Saa2 via targeted-placenta infusion will have higher efficacy and safety than via systemically infusion following sub-chronic maternal inflammation (Aim 2).The project will have a significant impact on the field of maternal-fetal medicine as it will provide placental SAA2 as a potential therapeutic target and will demonstrate a novel targeted-delivery route of siRNA to the placenta for the treatment of MI induced PTB and associated fetal brain injury.