Pharmacogenetics of antenatal corticosteroids to improve neonatal outcomes

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DESCRIPTION (provided by applicant): Preterm birth is on the rise and leads to significant neonatal mortality and morbidity. The expanding field of pharmacogenetics promises to improve physicians' ability to care for these patients. In this proposal, Dr. David M. Haas proposes a comprehensive five-year period of mentored training in patient-oriented clinical research aimed at improving neonatal outcomes stemming from preterm birth through pharmacogenetics. Candidate: Dr. Haas is a general OB/GYN physician who possesses basic research skills and has already published two background articles in this research area. His long-term objective is to become an independent investigator in obstetrics and gynecology with a research focus on preterm labor and improving obstetric outcomes through pharmacogenetics. There is a need for new, wellqualified researchers in this clinical field. Environment: Under the mentorship of Dr. David Flockhart, an internationally recognized investigator, and a panel of excellent co-mentors and advisors, Dr. Haas will pursue focused clinical research and will receive formal and practical instruction in all aspects of clinical investigation. The rich academic environment of the Indiana University School of Medicine (IUSM) is committed to Dr. Haas's development as an independent physician scientist and has a strong history of mentoring young investigators. As part of his K23 plan, Dr. Haas will complete the IUSM Clinical Investigator Training Enhancement program which will lead to a Masters of Science in Clinical Research degree. This will be accompanied by pharmacogenetics and laboratory training, developmental seminars, and training in research ethics. Research: The objective of this application is to evaluate pharmacogenetic variations that may lead to altered neonatal outcomes in response to antenatal corticosteroids in preterm labor. The central hypothesis is that pharmacogenetic differences in the glucocorticoid receptors and metabolic pathway correlate with outcome disparities and may help determine optimal antenatal corticosteroid dosing regimens. The two-phased research plan tests that hypothesis and will 1) Test for associations between gene sequence variations in the cytochrome P450 and sulfotransferase enzymes and neonatal outcomes, and 2) Test for associations between gene sequence variations in the glucocorticoid pathway and variation in pharmacodynamic response to antenatal corticosteroids. The research is significant in that improved pharmacogenetic understanding of glucocorticoid metabolism and function in preterm labor and neonatal respiratory function may help lead to improved outcomes and better treatment regimens. These studies will lay the foundation for future research designed to translate pharmacogenomic findings into improved treatment regimens for women with preterm labor. Relevance to public health: Consequences of preterm birth significantly impact families and society. Improving neonatal outcomes from preterm birth can reduce this impact. The ultimate goal of this K23 award is for Dr. Haas to become an independent clinical researcher focused on improvements in maternal and infant health outcomes from preterm labor and other conditions.