The Role of Corticotrophin Releasing Hormone on Placental Transcriptional Networks and Birth Timing

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PROJECT SUMMARY My long-term career objective is to establish an independent line of research using data driven, integrated approaches to examine parturition, and my interests lie within glucocorticoid signaling in pregnancy. Corticotrophin releasing hormone (CRH) is a peptide hormone involved in glucocorticoid signaling that is also produced by the placenta. CRH influences placental growth and function, modulates maternal metabolism, and is crucial for fetal development. Placental CRH is released into maternal plasma over the course of gestation, peaking before parturition, and elevated CRH in mid gestation is predictive of preterm birth. The central hypothesis of this proposal is that CRH levels in mid pregnancy alter the placental gene expression landscape, with downstream consequences on placental function and gestational length. This multidisciplinary project will bring together co-mentors who are key experts in their respective fields; Dr. Nathan Price (systems biology), Dr. Sheela Sathyanarayana (epidemiology) and Dr. Louis Muglia (endocrine regulation of pregnancy). Through software developed within in the Price lab, we have generated a large scale transcriptional regulatory network (TRN) of the human placenta. In this proposed analysis, we will expand this TRN to identify shared transcriptional drivers related to both maternal plasma CRH and gestational length, using samples from the University of Washington ECHO PATHWAYS. In aim 1, we will generate a genome wide, placental specific model quantifying relationships between transcription factors and their target genes, and validate this model using CRISPR/Cas9 technology to edit key transcription factors and quantify changes in downstream gene expression. In aim 2, we will identify genes related to CRH measured in mid to late gestation as well as genes related to gestational age, then identify overlapping genes and enriched biological pathways related to these genes. In aim 3, we will leverage the TRN to identify TF modules (networks of genes whose expression coordinately changes through a common transcription factor) which are related to the differentially expressed genes identified in aim 2, which we will validate in vitro through placental derived cell lines. In this way, we will identify shared transcriptional modules related to maternal plasma CRH and gestational length. We anticipate that this data driven study will uncover molecular mechanisms involving CRH's role in partition and gestational length, and provide potential targets to lengthen gestational length in pregnancies complicated by preterm birth. Additionally, this work will provide me with the background needed to establish an independent line of research.