More than 1 in 8 babies in the US are born preterm. Although medications such as 17-alpha hydroxyprogesterone caproate (17OHPC) and indomethacin can prevent and arrest SPTB in some women, >50% of women who receive these medications will still deliver preterm. Reasons for variable responsiveness are poorly understood, but may be due to genetic factors. This career development award is designed to support the transition of a promising, physician into an independent clinician-scientist dedicated to the study of the pharmacogenomics of spontaneous preterm birth (SPTB). Dr. Manuck has the enthusiastic support of her Division, Department, and Institution, including at least 75% protected time and appropriate institutional funding. This proposal outlines a training and research program that will provide 5 years of protected mentored time and transition Dr. Manuck into an independent and self-sustaining clinician-scientist. The specific career development aims are to: (1) expand existing skills in study design, analysis, and interpretation of results, (2) develop additional skills in the acquisition, management, and analysis of genetic and pharmacogenomic data, (3) develop additional skills in the design and implementation of clinical trials, (4) develop skills for leadership of a multi-disciplinary research team, and (5) further understanding of ethical and legal implications of perinatal genetics research. These goals will be achieved through a combination of regular meetings with mentors (Drs. Michael Varner, Robert Silver, and Lynn Jorde), completion of several research certificates and courses, collaboration with SPTB experts nationwide in the NICHD Genomics and Proteomics Network for Preterm Birth Research (GPN), and attendance at national meetings. The specific research aims/hypotheses are: (1) Variation in response to 17OHPC for the prevention of recurrent SPTB results from genetic variation within the Human Progesterone Receptor (2) Variation in response to 17OHPC for the prevention of recurrent SPTB is associated with genetic variation in Cytochrome P450 (CYP) - 3A, and (3) Variation in response to 17OHPC (SPTB prevention) and indomethacin (SPTB treatment) is associated with genetic variation in inflammatory pathways. These hypotheses will be tested by analyzing biologic samples (DNA and vaginal swabs) and clinical outcome data on over 1500 women witeh1 SPTB and 1000 controls with only term deliveries from the prospectively collected GPN. Patients have been recruited, data have been collected, and DNA extracted. Thus, this study design represents a feasible, efficient, and cost-effective method for a patient-oriented career development award investigating the pharmacogenomics of SPTB prevention and treatment. This proposal represents a unique opportunity to gain multi-disciplinary training and research experience while correlating genetic polymorphisms with well-characterized pregnancy outcomes in a large cohort, and will support this Clinician-Scientist's goal of becoming a national expert in the pharmacogenomics of SPTB.
This proposal will contribute to increased understanding of SPTB therapies by identifying the subset of women most likely to respond to 17OHPC and indomethacin, which will allow us to work towards individualizing treatment, maximizing benefit and limiting side effects. This has the potential to lead to key intervention trials among other groups of pregnant women. These advances may result in individualized preterm birth interventions, which in turn could lower the overall rate of both primary and recurrent SPTB and its corresponding neonatal morbidity and mortality.
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