MOLECULAR BIOLOGY OF UTERINE FUNCTION DURING PREGNANCY

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Edward K.S. Chien, M.D., received a baccalaureate degree in chemical engineering in 1984 and a medical degree in 1988 from the University of Illinois. Following his residency in Obstetrics and Gynecology at the University of Michigan Medical Center he completed a clinical fellowship in Maternal Fetal Medicine under the direction of Mark Phillippe, M.D., at the University of Chicago. During his clinical fellowship he worked in the laboratory of Dr. Mark Phillippe and investigated signal transduction mechanisms of myometrial cells. Two years ago Dr. Chien applied and received a Reproductive Scientist Development Program award. During that period of time he identified gestational regulated genes in the myometrium using differential messenger RNA display under the guidance of Dr. Graeme I. Bell, PhD. From these preliminary studies Dr. Chien has developed an extensive list of candidate genes which appear to be gestationally-regulated. The sponsor in the present application, Dr. Graeme Bell, is an international authority on monogenic and polygenic forms of diabetes mellitus and identified a number of transcription factors associated with maturity onset diabetes of the young. He has worked closely with Dr. Chien on all aspects of the present project. The broad, long-term objectives of this proposal is to identify and confirm, myometrial specific, gestationally-regulated genes and to understand the mechanisms surrounding their regulation. More specifically, the myometrium undergoes marked changes during pregnancy with significant changes in gene expression. The molecular mechanism behind these changes are to be identified. The regulatory elements of myometrial specific genes undergoing differential expression during pregnancy will be identified. These elements will be evaluated to determine their role in the changes related to pregnancy. Understanding the mechanism regulating changes in myometrial function will permit the development of novel therapies to treat preterm labor and post term pregnancies. The methods used to identify gestationally-regulated genes include differential mRNA display, cDNA array hybridization, and proteome analysis. Genomic sequences will be obtained by bacteriophage library screening after confirming tissue specific regulation with Northern blots and semi-quantitative reverse transcription-polymerase chain reaction. Regulatory regions are identified by cell transfection experiments with reporter gene constructs.