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

确定患有严重先兆子痫的非洲血统女性的胎盘损伤途径

• 批准号: 10742342
• 负责人: Omonigho Augustina Aisagbonhi
• 金额: $ 43.45万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10742342
• 关键词: Address; Affect; African; African American; African ancestry; Asian; Asian ancestry; Cell physiology; Cells; Chromosome Mapping; Data Analyses; Data Set; Disease; Early identification; Epitopes; Etiology; European; European ancestry; Evolution; Functional disorder; Gene Expression Regulation; Genes; Genotype; Goals; HLA Antigens; Health; Heart failure; Hypertension; IL3RA gene; Immune; Immunohistochemistry; Immunologics; Injury; Killer Cells; Life; Maternal Mortality; Mission; Molecular; Morbidity - disease rate; Natural Killer Cells; Oocyte Donation; Outcome; Pathology; Pathway interactions; Patients; Persons; Placenta; Placenta Diseases; Placentation; Play; Pre-Eclampsia; Pregnancy; Pregnancy Outcome; Pregnancy loss; Prevention; Process; Proteins; Public Health; Pulmonary Edema; RNA; Research; Risk; Role; Signal Pathway; Stroke; TAP1 gene; Testing; United States National Institutes of Health; Up-Regulation; Woman; World Health Organization; cell type; design; differential expression; digital; disability; fetal; health disparity; immune activation; immunoregulation; improved; innovation; insight; interest; normotensive; pathophysiology of preeclampsia; patient population; peripartum cardiomyopathy; protein expression; receptor; stroke-like outcome; study population; targeted treatment; therapeutic target; transcriptome sequencing; transcriptomics; trophoblast; Address; Affect; African; African American; African ancestry; Asian; Asian ancestry; Cell physiology; Cells; Chromosome Mapping; Data Analyses; Data Set; Disease; Early identification; Epitopes; Etiology; European; European ancestry; Evolution; Functional disorder; Gene Expression Regulation; Genes; Genotype; Goals; HLA Antigens; Health; Heart failure; Hypertension; IL3RA gene; Immune; Immunohistochemistry; Immunologics; Injury; Killer Cells; Life; Maternal Mortality; Mission; Molecular; Morbidity - disease rate; Natural Killer Cells; Oocyte Donation; Outcome; Pathology; Pathway interactions; Patients; Persons; Placenta; Placenta Diseases; Placentation; Play; Pre-Eclampsia; Pregnancy; Pregnancy Outcome; Pregnancy loss; Prevention; Process; Proteins; Public Health; Pulmonary Edema; RNA; Research; Risk; Role; Signal Pathway; Stroke; TAP1 gene; Testing; United States National Institutes of Health; Up-Regulation; Woman; World Health Organization; cell type; design; differential expression; digital; disability; fetal; health disparity; immune activation; immunoregulation; improved; innovation; insight; interest; normotensive; pathophysiology of preeclampsia; patient population; peripartum cardiomyopathy; protein expression; receptor; stroke-like outcome; study population; targeted treatment; therapeutic target; transcriptome sequencing; transcriptomics; trophoblast

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.

摘要/摘要 非洲血统的女性死于先兆子痫的可能性更高，这是妊娠引起的 高血压障碍或遭受中风，肺水肿和心力衰竭等不良结果，而不是 亚洲或欧洲的祖先。胎盘在递送的胎盘病理学中起着核心作用 通常是治愈的。但是，胎盘如何在非洲血统和 对哪些特定的胎盘损伤途径可能被靶向治疗，但研究不太精心研究。令人兴奋的演变 在阐明先兆子痫的潜在病理生理学时，疾病有多个 在胎盘中表现不同的病因。因此，本研究的目的是确定特定 胎盘细胞和分子损伤途径可能会导致不成比例的情况差。 与欧洲和亚洲祖先的妇女相比，非洲血统的妇女。最终目标是 确定胎盘损伤的途径，可以针对改善非洲妇女的怀孕结局 祖先。中心假设是免疫过程，包括非允许的HLA 与免疫激活相关的基因的不匹配和上调是 与亚洲妇女相比 和欧洲血统。该假设将以两个具体的目的进行检验：1。确定区域和细胞 - 基因和途径的特定定位，这些基因和途径在患有胎盘中差异表达/改变 与亚洲和亚洲妇女相比 欧洲祖先使用数字空间转录组学，并评估胎盘免疫细胞环境如何 这些患者种群使用免疫组织化学的变化。 2。评估母亲fetal HLA的作用 HLA分子在严重的先兆子痫病理生理学中的不匹配和胎盘表达改变 在非洲血统与亚洲和欧洲祖先的妇女中，使用综合HLA 基因分型，HLA功能预测分析和免疫组织化学。拟议的研究是 从概念上创新，因为它将针对女性的严重先兆子痫的病理生理 非洲血统（与亚洲和欧洲祖先的妇女相比） 该疾病的胎盘表现。它在技术上是创新的，因为它将集成两个RNA分析 （通过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，这些过程可能是治疗靶标的 调节非洲血统妇女严重的先兆子痫的结果更糟。此外，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免疫组织化学，以更好地了解非允许HLA的病因贡献 与非洲血统女性严重先兆子痫的病理生理不匹配。