Principal Investigator: WILLIAM LARSEN
Abstract: Preterm labor is a major cause of infant mortality in the United States and results in major medical expenditures for the care of surviving infants. The successful design of therapies to prevent preterm labor in patients at risk or to inhibit preterm myometrial contraction once they have begun requires a greater understanding of the cellular mechanisms which underlie human preterm labor. One pivotal cellular event in the cascade which brings about productive myometrial contractions in both preterm and normal term labor is the rapid and dramatic development of a functional population of myometrial gap junctions in the final 24-72 hours prior to parturition. Shortly after parturition, this population of gap junctions disappears. Although this relationship has been well established in a wide variety of species, including the human, and general hormonal controls have been investigated, much useful information regarding relationships between gap junction protein metabolism, gap junction assembly and their removal from the membrane, and the development of synchronous contractile activity remains to be elucidated. New knowledge of many of the mechanisms which underlie the modulation of gap junction subunits and the recent development of a radioimmunoassay for gap junction proteins offer the opportunity to investigate these relationships with greater efficiency and in greater detail. We intend to investigate these question by first adapting a radioimmunoassay for gap junction protein in the liver to the 43K Da and 21K da gap junction proteins known to occur in the myometrium. This new technology will then be utilized with existing morphological techniques such as freeze fracture, and transmission electron microscopy, to study the sequence of gap junction protein synthesis, assembly of junctional aggregates, and junctional endocytosis in the term rat myometrium. These studies will be carried out over a wide time course with particular attention to the final 96 hours prior to delivery. These relationships will then be compared to those occurring in several different models of preterm labor including the ovariectomized rat, and in animals injected with estradiol, RU 486, prostaglandins and indomethacin. Finally, biopsies of preterm and term, non-contracting and contracting human myometrium will be analyzed to determine how and to what degree the modulation of gap junction proteins in the human compares with the rat. This human tissue will also be utilized to develop cell cultures to further test modulatory effects of a variety of physiological and pharmacological agents on the initiation, and rate of gap junction protein synthesis and gap junction assembly, and endocytosis. Data obtained in these studies should provide a fundamental basis for the development of new preventative therapies and risk assessment for preterm labor.
Funding Period: 1989-09-01 - 1992-08-31
more information: NIH RePORT