Identification of Cell-Specific Transcriptional Programs that Drive Cervical Remo

点击翻译按钮获取中文摘要

Premature Birth (PTB) is the most common complication during pregnancy leading to a high incidence of perinatal morbidity and mortality rates in developed countries. According to the CDC, in 2018, 1 of every 10 newborns delivered preterm in the United States. An understanding of the molecular processes that determine a successful pregnancy and on time parturition is essential in order to elucidate the diverse mechanisms by which this process can go awry and lead to a premature birth. The transformation of the cervix from a closed rigid structure to one that can open sufficiently for passage of a term infant is one such process. The significance of the proposed studies is the potential to advance understanding of the dynamic molecular events that regulate cervical remodeling at the cellular level. The focus of this application is to utilize innovative single cell genomic technologies that will allow us to define gene regulatory networks that drive cervical remodeling. We will identify regions of active transcription at single cell resolution in the mouse cervix from nonpregnant, time points in pregnancy, and in labor. Utilizing novel computational approaches previously used to study cellular reprogramming events in development, this data will be used to understand how each cell type transitions its phenotype to implement the dynamic process of remodeling and identify the cell specific transcription factors that drive these cell specific molecular changes. Functional validation of the identified transcription factors will be carried out using a human 3D-cervical cell culture system and studies in normal mice and mouse models with targeted deletion of the transcription factors. The proposed studies will provide a solid and broad foundation of understanding of cellular events that drive cervical remodeling which will allow the discovery of risk factors for premature birth that are not yet known and will uncover new pathways to explore for therapeutic targets for prevention of preterm birth. In addition, these studies will provide me the scientific and technical knowledge required for a successful postdoctoral training and importantly, will set the foundation to apply for K awards aiding in my transition to becoming an independent investigator in the reproductive field.