Isolation of Human Paracrine Factor for Labor Inhibition

Preterm delivery before 37 weeks of gestation (PTD) is a major public health problem. There are 4.5 million deliveries in the US of which 11% occur prematurely. Despite extensive research and a multitude of interventions, the rate of PTD has actually increased over the past 20 years. No available labor inhibiting drug prolongs pregnancy more than 96h compared to placebo. High risk groups include substance abusers, adolescents, and members of low socioeconomic class and minorities. The refractory nature of the problem reflects its heterogeneous etiology and pathophysiology, which may require multiple distinct preventive and therapeutic approaches. Scientists based much of their past activities on the assumption preterm labor is the same as term labor, only ill-timed. One of the great reproductive mysteries is not why labor occurs at term, but why it does not occur much earlier in gestation in response to progressive stretching of the myometrium in response to the growing conceptus. Four myometrial phases are described across gestation: quiescence, activation, labor and involution. We suggest myometrial quiescence is an active process and have demonstrated a paracrine uterine quiescent factor (QF) that is synthesized and released from human and guinea pig chorion with biologic characteristics consistent with having principle reponsibility for uterine quiescence. Withdrawal of the QF would lead to premature myometrial activation and susceptability to preterm labor, and continued release at term would produce dysfunctional labor or post dates culminating in cesarean section and its attendent morbidity and costs. We propose 3 specific aims for a Phase I study. 1 - Isolate QF using traditional gel electrophoretic approaches and mass spectrometry; 2 - Protein characterization of QF; 3 - Synthesize or purify QF. We will then move rapidly, in Phase 2, to translational studies beginning with a test of the ability of either native or synthesized QF to inhibit preterm delivery in guinea pig. The outcome of this research will provide a deeper understanding of gestational regulation and lead to new targeted therapies to prevent PTD and reduce cesarean section for dysfunctional labor.