Infection accounts for 25-40% preterm births in the United States and is the primary cause of preterm birth in underdeveloped countries. Evidence that preparation for parturition begins early in pregnancy and that mechanisms of preterm birth are distinct from term and dependent on etiology, emphasize the need to define pathway specific regulatory mechanisms. Cervical remodeling - the process by which the cervix is transformed from a closed rigid structure to one that can open to allow passage of a term fetus through the birth canal - is a key component of the birth process that precedes onset of uterine contractions in term and preterm birth. A better understanding of mechanisms that drive term and infection-mediated preterm cervical remodeling will provide new insights that can be used for the detection and prevention of PTB. The processes that govern cervical remodeling in term or preterm birth are regulated at (1) the transcriptional level by the expression of mRNAs, microRNAs, and long non-coding RNAs (lncRNAs) and (2) the post-transcriptional level by the actions of miRNAs on target mRNAs and ncRNAs. The integration of these mechanisms forms a regulatory circuit that allows finely tuned and carefully coordinated gene expression programs. The identification of clinically relevant interactions between microRNAs and their target mRNAs and lncRNAs in relevant biological models, will provide new insights into the biological mechanisms that mediate premature cervical ripening. The goal of the current study is to computationally interrogate recently generated cervical polyA+ RNA-Seq and microRNA microarray datasets from term and infection-mediated preterm mouse models to identify regulated microRNAs and their predicted mRNAs and lncRNA targets. A 3D-human cervical stromal cell culture system and cell based gene specific assays will be established in order to validate ~ 10 microRNA:target RNA interactions that will be selected using specific criteria such. Finally the impact of an infection-mediated preterm birth on postpartum cervical repair and cervical function/risk of prematurity in a second pregnancy will be investigated comprehensively using tissue biomechanics, physiology as well as cutting edge imaging and genomic approaches. Collectively these studies will dissect the molecular pathways that regulate processes critical for successful parturition at term and define the regulatory circuits that go awry in infection-mediated preterm birth.
Understanding the molecular processes that modulate infection-mediated premature cervical remodeling is critical to the identification of therapeutic targets and the development of improved tools for early risk detection. The focus of this application is to utilize mouse cervical RNA-profiling data to identify microRNA interactions with target mRNA or long noncoding RNAs that regulate infection-mediated premature cervical ripening and to investigate mechanisms by which premature cervical ripening increases risk of prematurity in a subsequent pregnancy. Collectively these studies will provide new avenues to accurately diagnose and treat infection- mediated preterm birth.
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