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.