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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

基本信息

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
项目类别：
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

项目摘要

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/文摘