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，而不是由于先天畸形。 早产的发生率在过去几十年里有所上升，直到最近才稳定下来。这个 最有效的预防早产的治疗(产妇服用黄体酮)适用 仅适用于少数注定要早产的患者(即先前早产或患有早产的患者 缩短宫颈)，不能用于已经分娩的患者。目前的建议旨在利用 小鼠感染和炎症模型的研究结果显示，外源性黄连有很强的抗产作用。 注射表面活性蛋白A(SP-A)，这是一种由胎儿和母体组织产生的蛋白质。更新的数据 提示即使在全身(即静脉注射)和数小时内给予SP-A，这种影响仍然存在 在引产刺激站稳脚跟后，区分对于潜在的临床应用是重要的。这 提案将涉及研究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(S)(即最小功能单元，或MFU)，用于其抗产和抗炎 产程中因活体细菌感染或无菌炎症状态而产生的炎症功能 2)评估SP-A mfu在小鼠及其后代中的安全性；以及3)检验以下假设 SP-A的上述作用依赖于Toll样受体2及其下游信号的参与 转导机制。作为一种由发育中的胎儿产生的内源性蛋白，SP-A很可能具有 极佳的安全性能。该项目将为开发SP-A作为预防性或 人类早产的治疗剂，从而为节育提供了潜在的新机会 家庭和社会关注早产的发病率、痛苦和成本。

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.