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

胎盘血清淀粉样蛋白 A 作为预防早产和早产相关发病的治疗靶点

基本信息

批准号：
10742411
负责人：
IRINA BURD
金额：
$ 42.49万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-15 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10742411
关键词：
37 weeks gestation Acute Age Animals Binding Biological Markers Birth Birth Rate Blood Vessels Blood flow Brain Cell Death Cervix Uteri Child Clinical Data Developed Countries Development Disease Dose Etiology Exposure to Family Fetal Tissues Fluorescence Genes Goals Harvest Healthcare Immune Immune response Infection Inflammation Inflammatory Inflammatory Response Infusion procedures Injury Interleukin-1 beta Intravenous Label Link Maternal-fetal medicine Mediating Mediator Methodology Morbidity - disease rate Mothers Neurologic Organ Outcome Pathogenesis Pathologic Perinatal Placenta Play Predisposition Premature Birth Premature Infant Prevention Prevention strategy Process Protein Isoforms Proteins Publishing RNA Interference RNA Interference Therapy Recovery Reporting Research Risk Role Route Safety Serum Serum amyloid A protein Small Interfering RNA Societies Structure Technology Therapeutic Therapeutic Agents Tissues United States Uterus Weaning behavior test care costs cytokine fetal fetal brain injury fetal loss high reward high risk in vivo imaging innovation intraperitoneal lipid nanoparticle mortality mouse model neonate novel novel therapeutic intervention offspring overexpression perinatal outcomes personalized medicine placental morphology preclinical study premature prenatal exposure prevent receptor reproductive system disorder response side effect targeted delivery therapeutic RNA therapeutic target

项目摘要

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.

概括早产 (PTB) 和相关的胎儿脑损伤会导致不良的围产期结局，包括后代死亡率以及家庭和社会的护理和治疗费用高昂。病理性免疫母体炎症 (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，其机制仍不清楚。结构和功能。为此，缺乏能够保护患者健康的治疗药物。暴露于 MI 的后代。血清淀粉样蛋白 A (SAA) 已被确定为一种炎症生物标志物尚未在 MI 的背景下研究其病理作用。我们公布的数据表明，一同种型，SAA2 在胎盘发育过程中不存在，但对急性母体感染高度敏感炎。在本提案中，我们计划研究胎盘 SAA 亚型在响应亚型中的作用慢性 MI 并探索使用小干扰 RNA (siRNA) 系统性抑制 Saa2 是否可以缓解 PTB 和不良后代结局（目标 1）。此外，我们将比较效果通过靶向胎盘输注对 Saa2 施用 siRNA 比通过胎盘输注具有更高的功效和安全性在亚慢性母体炎症后进行全身输注（目标 2）。该项目将产生重大影响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 siRNA 靶向递送途径至胎盘，用于治疗 MI 诱发的心肌梗死 PTB 和相关的胎儿脑损伤。