Premature birth (PTB) is the most common complication of pregnancy affecting families worldwide and is the leading cause of perinatal morbidity and mortality in developed countries. The long-term research goal is to define critical physiological and genetic pathways that regulate labor at term and preterm in order to treat and prevent PTB. During the parturition process, the myometrium becomes highly contractile and excitable to produce the coordinated and forceful contractions of labor in response to inflammatory signals and prostaglandins. Of note, infection and infection-driven inflammation may contribute to 25?40% of preterm births. A common element of both idiopathic and infection-mediated preterm is the presence of an inflammatory state. Inflammatory responses in different cell types share a common set of well-coordinated molecular events that lead to the expression of proinflammatory cytokines and other proinflammatory proteins. In many disease states, extensive cellular stress triggers uncontrolled poly(ADP-ribose) polymerase-1 (PARP-1) activation. Early studies showed that PARP-1 null mice are resistant to septic shock and more recent studies have highlighted the roles of PARP-1 in response to inflammatory stress signals. This application is specifically focused on characterizing the role of PARP-1 in mediating the myometrial response to pathological (LPS)-mediated inflammation and contractility. Guided by strong preliminary data and promising results using PARP inhibitors (PARPi) to treat inflammatory disease, three specific aims are proposed: (1) determine the extent of PARP-1 activity in PTB and explore PARPi as a potential therapeutic in delaying the onset of labor; (2) determine the impact of PARP-1 on uterine physiology in response to LPS-mediated PTB; and (3) determine the role of PARP-1 in mediating transcription factor function. An integrative approach employing a combination of mouse models, genomics, and proteomics will be used to elucidate the role of PARP-1-dependent mechanisms regulating myometrial physiology and PTB. The proposed aims are conceptually and technically innovative and together will have a broad impact on the field by filling a substantial gap in our fundamental knowledge of uterine biology and PTB. In addition, the current proposal will allow me to gain technical expertise in (1) state-of-the-art genomic methodologies (PRO-seq and ChIP-seq), (2) novel methods to study PARPs (ADPR-detection reagents, asPARP mass spec) and (3) advanced computational methods. Further, the Kraus lab and UT Southwestern Medical Center provides an environment that will facilitate my growth as a scientist and successful transition to becoming an independent investigator
Premature birth (PTB) is the leading cause of perinatal morbidity and mortality in developed countries, and infection-driven inflammation is a major underlying contributor to PTB. Recent studies have highlighted a critical role of Poly(ADP-ribose) polymerase-1 (PARP-1) in regulating inflammatory responses in numerous biological contexts. The proposed studies will have a significant impact in the field of female reproductive biology by revealing the mechanisms controlled by PARP-1 activity that mediate the inflammatory response of the myometrium and lead to premature labor and PTB.
