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

总结 早产（PTB）和相关的胎儿脑损伤会带来不良的围产期结局，包括 后代死亡率高，家庭和社会的护理和治疗费用高。病理免疫 母体炎症（MI）期间胎盘的反应被认为是PTB的主要原因， 围产期后遗症然而，由于胎盘的复杂性，其机制仍然没有很好地理解。 结构和功能。为此目的，缺乏能够保护肿瘤细胞的治疗剂。 暴露于MI的后代。血清淀粉样蛋白A（SAA）已被鉴定为炎症生物标志物， 其病理作用尚未在MI的背景下进行研究。我们公布的数据表明， 同工型，SAA 2在胎盘发育中不存在，但对急性母体感染高度敏感。 炎症在这项提议中，我们计划研究胎盘SAA亚型在对亚急性胰腺炎的反应中的作用。 慢性MI，并探索使用小干扰RNA（siRNA）系统性抑制Saa2是否会 PTB和不良后代结局（目标1）。此外，我们将比较是否 通过靶向胎盘输注给予Saa2 siRNA将比通过胎盘输注给予Saa2 siRNA具有更高的功效和安全性。 在亚慢性母体炎症后全身输注（目标2）。该项目将具有显著的 对母胎医学领域的影响，因为它将提供胎盘SAA 2作为潜在的治疗靶点 并将证明一种新的靶向递送途径的siRNA的胎盘治疗心肌梗死诱导 PTB和相关的胎儿脑损伤。

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.