Preterm birth is the most common cause of perinatal morbidity and mortality not due to congenital anomalies. The incidence of preterm delivery has risen over the last several decades and only recently has stabilized. The most impactful treatment proven to prevent preterm birth (maternal administration of progesterone) applies only to a minority of patients destined to deliver prematurely (i.e. those with a prior preterm birth or with a shortened cervix), and cannot be used in patients already in labor. The present proposal seeks to capitalize on findings from a mouse model of infection and inflammation showing a powerful anti-labor effect of exogenously administered surfactant protein A (SP-A), a protein produced by fetal and maternal tissues. Newer data suggest that this effect persists even when SP-A is administered systemically (i.e. intravenously) and hours after the labor-inducing stimulus has taken hold, distinctions that are important for potential clinical use. This proposal will address three objectives in studying SP-A to prevent preterm birth: 1) Identify the crucial domain(s) of the SP-A molecule (i.e. the minimal functional unit, or MFU) for its anti-labor and anti- inflammatory functions during labors due to either live bacterial infection or sterile inflammatory states in the mouse; 2) Assess the safety of the SP-A MFU in mice and their offspring; and 3) Test the hypothesis that the above effects of SP-A are dependent upon engagement of toll-like receptor (TLR) 2 and its downstream signal transduction mechanisms. As an endogenous protein produced by the developing fetus, SP-A is likely to have an excellent safety profile. This project will lay the groundwork for developing SP-A as a preventive or therapeutic agent for preterm labor in humans, thereby providing potential new opportunities for sparing families and society the morbidity, suffering and costs of premature birth.

Project Narrative The incidence of preterm delivery in the US remains unacceptably high and has only recently stabilized. The current proposal takes advantage of exciting new discoveries in the laboratory to assess the potential of a novel therapy for prevention of preterm birth, thereby providing an opportunity to diminish the toll of prematurity for individuals, families and society.