Prevention of Preterm Birth Using the Collectin Surfactant Protein A (SP-A)

早产是围产期发病率和死亡率的最常见原因，而不是由于先天性异常。 早产的发生率在过去几十年中有所上升，直到最近才稳定下来。的 最有效的治疗证明，以防止早产（孕激素的母亲管理）适用 仅适用于少数注定早产的患者（即先前早产或 缩短的宫颈），并且不能用于已经分娩的患者。本提案旨在利用 来自感染和炎症的小鼠模型的发现显示了外源性 施用表面活性剂蛋白A（SP-A），一种由胎儿和母体组织产生的蛋白质。较新的数据 表明即使全身（即静脉内）给予SP-A，这种作用也持续数小时 在诱发分娩的刺激已经站稳脚跟之后，这些区别对于潜在的临床应用是重要的。这 该提案将解决研究SP-A以预防早产的三个目标：1）确定关键的 SP-A分子的结构域（即最小功能单元，或MFU），用于其抗分娩和抗- 由于活细菌感染或无菌炎症状态， 小鼠; 2）评估SP-A MFU在小鼠及其后代中的安全性;和3）测试SP-A MFU在小鼠及其后代中的安全性的假设。 SP-A的上述作用依赖于Toll样受体（TLR）2及其下游信号的参与 转导机制作为发育中的胎儿产生的内源性蛋白，SP-A可能具有 安全性能极佳这一项目将为制定特别方案-A作为预防或 用于人类早产的治疗剂，从而提供了潜在的新机会， 早产的发病率、痛苦和成本对家庭和社会都有很大影响。

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.