Identifying placental injury pathways in women of African ancestry with severe preeclampsia

摘要/摘要 非洲血统的妇女死于先兆子痫的可能性是非洲血统妇女的3到5倍， 高血压疾病，或遭受不良后果，如中风，肺水肿和心力衰竭， 亚洲或欧洲血统。胎盘在子痫前期的病理学中起着核心作用， 往往是治愈性的。然而，胎盘如何导致非洲血统女性的不良结局，以及 哪些特定的胎盘损伤途径可以作为治疗的靶点还没有很好的研究。令人兴奋的进化 在阐明先兆子痫的潜在病理生理学中， 在胎盘中表现不同的病因。因此，本研究的目的是确定具体的 胎盘细胞和分子损伤途径，可能导致不成比例的更糟糕的结果， 非洲血统的妇女与欧洲和亚洲血统的妇女相比。最终目标是 确定胎盘损伤的途径，可以有针对性地改善非洲妇女的妊娠结局 祖先核心假设是免疫过程，包括非允许性HLA 与免疫激活相关的基因的错配和上调是导致 非洲血统妇女与亚洲血统妇女重度先兆子痫的病理生理学比较 欧洲血统。这一假设将在两个特定的目标进行测试：1。识别区域和细胞- 特异性定位的基因和途径，差异表达/改变的妇女胎盘， 严重先兆子痫与非洲血统的血压正常妇女相比，与亚洲和 欧洲血统，使用数字空间转录组学，并评估胎盘免疫细胞环境 使用免疫组织化学检测这些患者人群的变化。2.评估母胎HLA的作用 重度子痫前期病理生理学中HLA分子的错配和胎盘表达改变 在非洲血统的女性与亚洲和欧洲血统的女性中，使用全面的HLA 基因分型、HLA功能预测分析和免疫组化。拟议的研究是 概念上的创新，因为它将解决严重先兆子痫的妇女的病理生理学， 非洲血统（与亚洲和欧洲血统妇女相比） 疾病的胎盘表现。它在技术上是创新的，因为它将整合RNA分析， (via RNA测序和数字空间转录组学）和蛋白质表达（通过免疫组织化学）， 确定胎盘细胞过程、基因和途径，这些过程、基因和途径可能成为治疗靶点， 调节非洲血统妇女严重先兆子痫的不良结局。再者是 其深度创新，因为它将包括全面的HLA基因分型、HLA功能预测 分析和HLA免疫组化，以更好地了解非允许性HLA的病因学贡献 与非洲血统妇女中重度先兆子痫的病理生理学不匹配。

Summary/Abstract Women of African ancestry are 3 to 5-times more likely to die of preeclampsia, a pregnancy-induced hypertensive disorder, or suffer bad outcomes like stroke, pulmonary edema and heart failure, than women of Asian or European ancestries. The placenta plays a central role in the pathology of preeclampsia, as delivery is often curative. However, how the placenta contributes to worse outcomes in women of African ancestry, and which specific placental injury pathways may be targeted for therapy, are not well studied. An exciting evolution in elucidating the underlying pathophysiology of preeclampsia is the concept that the disease has multiple etiologies that manifest differently in the placenta. Therefore, the aim of this study is to identify the specific placental cellular and molecular injury pathways that may account for the disproportionately worse outcomes in women of African ancestry in comparison to women of European and Asian ancestries. The ultimate goal is to identify pathways of placental injury that can be targeted to improve pregnancy outcomes in women of African ancestry. The central hypothesis is that immunologic processes, including non-permissive HLA mismatches and upregulation of genes associated with immune activation underlie the pathophysiology of severe preeclampsia in women of African ancestry compared to women of Asian and European ancestry. This hypothesis will be tested in two specific aims: 1. Identify the region and cell- specific localization of genes and pathways that are differentially expressed/altered in placentas of women with severe preeclampsia versus normotensive women of African ancestry, in contrast to women of Asian and European ancestries, using digital spatial transcriptomics, and evaluate how the placental immune cell milieu changes in these patient populations using immunohistochemistry. 2. Evaluate the role of maternal-fetal HLA mismatches and altered placental expression of HLA molecules in the pathophysiology of severe preeclampsia in women of African ancestry versus women of Asian and European ancestries using comprehensive HLA genotyping, HLA functional prediction analysis and immunohistochemistry. The proposed research is conceptually innovative because it will address the pathophysiology of severe preeclampsia in women of African ancestry (compared to women of Asian and European ancestries) from the context of differential placental manifestations of the disease. It is technically innovative because it will integrate both RNA profiling (via RNA sequencing and digital spatial transcriptomics) and protein expression (via immunohistochemistry) to identify placental cellular processes, genes, and pathways that will potentially be therapeutic targets to modulate the worse outcomes of severe preeclampsia in women of African ancestry. Furthermore, it is innovative in its depth because it will include comprehensive HLA genotyping, HLA functional prediction analysis and HLA immunohistochemistry to better understand the etiologic contribution of non-permissive HLA mismatches to the pathophysiology of severe preeclampsia in women of African ancestry.