Discovery of Novel Therapeutics for Inflammation Induced Preterm Birth

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PROJECT SUMMARY In this K99/R00 Pathway to Independence application, the candidate proposes a structured, rigorous and detailed training plan to build expertise in ex vivo gestational tissue modeling and preterm birth physiology along with continued education in the latest approaches for drug discovery. This training plan will be supported through hands-on-training, coursework, workshops, training in the responsible conduct of research, seminars and conferences. The candidate also proposes to gain experience in operating an independent research lab through grant writing workshops, networking and mentorship from a multidisciplinary advisory committee with expertise in obstetrics, reproductive sciences, neonatology, infectious disease and chemical biology/pharmacology, whom have long track records in training future independent researchers. The work in K99 phase will be completed at Vanderbilt University Medical Center, which has a plethora of resources and expertise available that perfectly aligned with the PI’s needs. The candidate`s primary goal is to establish a successful, independent research program that tests translational interventions aimed at management of infection-induced preterm labor (III-PTL). Preterm birth, defined as delivery before 37 weeks of gestation, is the leading worldwide cause of infant morbidity and mortality. Intrauterine infection and/or inflammation is a major trigger of early labor leading to preterm birth and fetal inflammation causing adverse neonatal outcomes. Unfortunately, there is a critical lack of therapeutics for the management of early labor that occurs as the result of infection/inflammation during pregnancy. Studies involved in the K99 and R00 phases of this proposal encompass novel approaches to identify effective therapeutic agents to manage III-PTL without adverse effects. Recent transcriptomic studies on gestational membranes have identified gene targets implicated in III-PTL and we have determined which of these genes are part of the druggable genome and could be explored for therapeutic regulation of III-PTL. In Aim 1 (K99) we will optimize a high-throughput screening (HTS) assay to measure changes in proinflammatory cytokines released from pathogen-associated molecular patterns (PAMP)-induced gestational membrane (GM) explants in 96-well format. We will utilize this HTS assay to screen a customized library of small-molecules that target the druggable transcriptome associated with III-PTL. We will perform a series of secondary screens to prioritize hit-molecules into leads. In Aim 2 (R00 phase), we will utilize a high-throughput combination screen to identify combination therapeutics with synergistic effects. In Aim 3 (R00 phase), mouse models of III-PTL will be used to confirm the in vivo ability of our lead-single or synergistic combinations to manage PTL and protect against fetal inflammation. The training plan and outstanding mentoring committee will ensure the success of the project and support the candidate’s career development towards the establishment of an independent research lab in the R00 phase.