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

使用集合素表面活性剂蛋白 A (SP-A) 预防早产

基本信息

批准号：
10403521
负责人：
EMMET HIRSCH
金额：
$ 34.87万
依托单位：
NORTHSHORE UNIVERSITY HEALTHSYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-11 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10403521
关键词：
Address Adverse effects Amniotic Sac Anti-Inflammatory Agents Antiinflammatory Effect Bacteria Bacterial Infections Baculoviruses Biological Birth Carbohydrates Cells Cervix Uteri Chronic Clinical Collectins Complex Connexin 43 Data Escherichia coli Exposure to Family Fetal Development Fetal Lung Fetal Viability Fetus Genetic Genotype Goals Growth Hand Hour Human In Vitro Incidence Individual Induced Labor Infection Inflammation Inflammatory Injections Innate Immune System Interleukin-1 beta Intravenous Knock-out Laboratories Length Ligand Binding Ligands Lipopolysaccharides MAP Kinase Gene Macaca Mediating Minority Modeling Monkeys Morbidity - disease rate Mothers Mus Myometrial N-terminal Neck Neonatal Neonatal Mortality Oxytocin Receptor Partner in relationship Patients Peptidoglycan Perinatal mortality demographics Pregnancy Premature Birth Premature Labor Prevention Prevention therapy Preventive Production Progesterone Proteins Pulmonary Surfactant-Associated Protein A Recombinant Proteins Recombinants Reporter Risk Safety Series Signal Transduction Site Societies Sterility Stimulus Streptococcus Group B Structure System TLR2 gene Testing Therapeutic Agents Tissues Toll-like receptors Variant cell type clinically relevant congenital anomaly cost experimental study fetal improved in vitro activity in vivo inflammatory marker instrument macrophage male microbial mouse model neonatal morbidity novel therapeutics offspring ovary transplantation p65 perinatal morbidity pregnant premature prevent receptor response vector

项目摘要

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.

早产是围产期发病和死亡的最常见原因，而非先天性异常。过去几十年来，早产的发生率有所上升，直到最近才趋于稳定。这已证明可预防早产的最有效的治疗方法（母亲服用黄体酮）适用仅适用于少数注定要早产的患者（即既往有过早产史或有过早产史的患者）缩短的子宫颈），并且不能用于已临产的患者。本提案旨在利用小鼠感染和炎症模型的研究结果表明，外源性药物具有强大的抗分娩作用给予表面活性剂蛋白 A (SP-A)，这是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）施用 SP-A 数小时，这种效果仍然持续引产刺激发生后，这些区别对于潜在的临床应用很重要。这该提案将解决研究 SP-A 预防早产的三个目标：1) 确定关键因素 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- 分娩过程中由于活细菌感染或无菌炎症状态而产生的炎症功能老鼠; 2) 评估SP-A MFU在小鼠及其后代中的安全性； 3) 检验假设 SP-A 的上述作用取决于 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质，SP-A 可能具有出色的安全性。该项目将为开发 SP-A 作为预防或预防措施奠定基础。人类早产的治疗剂，从而为避免早产提供潜在的新机会家庭和社会早产的发病率、痛苦和成本。