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Degree

Doctor of Philosophy

Program

Biochemistry

Collaborative Specialization

Developmental Biology

Supervisor

Han, Victor K.M.

Abstract

A normally developed placenta is integral to a successful pregnancy. Preeclampsia (PE) and intrauterine growth restriction (IUGR) are two common pregnancy related complications that result from abnormal placental development. Placental microRNAs (miRNAs) have been investigated as potential biomarkers for these complications, but they may also play a role in placental development and pathophysiology by influencing gene expression. The objectives of this study are (i) to utilize next-generation sequencing to determine miRNA and gene expression in human placental (chorionic villous) samples from three distinct patient groups with early-onset (EO) PE, IUGR, or PE + IUGR, and (ii) integration of expression datasets to assess the impact of dysregulated miRNAs on gene expression and trophoblast cell function.Placental tissues were collected from four patient groups (control [N=21], EO-PE [N=20], EO-IUGR [N=18], and EO-PE + IUGR [N=20]), and totalRNA was used for miRNA and RNA sequencing. Multiple differential expression analysis programs were used to analyze both expression datasets in each patient group compared to gestational age-matched controls. Inverse correlation analysis and target prediction software were used to identify gene targets. Candidate gene targets identified were confirmed using luciferase assays, and impact of miRNAs on trophoblast function was assessed using proliferation and migration assays in HTR-8/SVneo cells.Analysis revealed miRNAs and genes that are disease-specific, as well as others that are common between disease groups, 6 microRNAs and 22 genes were identified to be differentially expressed in all three patient groups. In addition, integrative analysis between the miRNA and gene expression datasets revealed candidate gene targets for miR-193b-5p and miR-210-5p, two miRNAs that also have an impact on trophoblast cell functions. Our findings suggest common underlying placental pathologies in EO-PE and EO-IUGR.Dysregulated miRNAs and genes identified in this study provide further evidence for trophoblast dysfunction in these pregnancy complications. Integration of miRNA and RNA profiling in the same three subgroups of pregnancy complications, provides an alternate level of molecular information and is a useful tool to expand our understanding of molecular perturbations in the placenta in early onset diseases.

Creative Commons License

Creative Commons Attribution-Noncommercial 4.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial 4.0 License

Available for download on Thursday, April 02, 2020

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