Dissecting gene dysregulation at the maternal-fetal interface in preeclampsia

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Abstract. The goal of the proposed research is for Dr. Alejandra Elder Ontiveros to obtain additional training in reproductive biology at the postdoctoral level. She received her MD degree from Escuela de Medicina Ignacio A. Santos, Instituto Tecnologico y de Estudios Superiores de Monterrey. Under the mentorship of Dr. Richard Behringer (Baylor College of Medicine), she recently completed her doctoral work studying uterine development in mice. Then she moved to the laboratory of Dr. Susan Fisher (University of California San Francisco, UCSF) where she is learning human placental biology and a powerful -omics technology—mass spectrometry (MS). In the award to which this supplement is appended, the Fisher group is testing the hypothesis that global gene expression profiling of cytotrophoblasts (CTBs) from placentas of preeclampsia (PE) patients will lead to the identification of novel molecules that play important roles in this syndrome. The impetus for this strategy is the finding that PE is consistently associated with aberrant differentiation of these cells, which translates into shallow placentation and the maternal signs of this syndrome. During the current segment of this R37 award, the group is using single cell sequencing to reveal disease-associated alterations in the developmental trajectories of differentiating CTBs. The goal of the experiments proposed in this application is to characterize the proteomes of CTBs isolated from the placentas of PE patients and control women, the same cells that are being subjecting to single-cell sequencing. The results will enable the addition of significant new dimensions to the latter work. First, the data will extend the findings from the mRNA to the protein level, important given the frequent lack of concordance between the two. Second, immunolocalization of the differentially expressed molecules in both datasets will pinpoint the exact location where the affected cells reside. This information will enable formulation of strategies for future experiments designed to test their functions. To further her career development, she will take classes (e.g., MS, bioinformatics, statistics, grant writing, mentorship and career advancement) and seek additional training experiences (e.g., responsible conduct of research, diversity and outreach). To hone her communication skills, she will regularly give presentations at UCSF and national meetings. Her research and career development will be overseen by an outstanding team of senior faculty with the relevant expertise indicated: Dr. Linda Giudice (human uterine biology, endometriosis, infertility), Dr. Robert Blelloch (cancer biology and immunology, mouse placental biology) and Dr. Steven Hall (mass spectrometry, including instrumentation and data analysis). All have distinguished mentoring and training records; two are physician scientists (Drs. Giudice and Blelloch). Their commitment to the candidate and the enthusiastic support of her primary mentor, Dr. Fisher, ensure the success of the training plan and the eventual launch of the candidate’s independent career as a faculty member and principal investigator at a top-tier medical research institution.