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

• 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
• 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

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.

早产是围产期发病率和死亡率的最常见原因，而不是由于先天性异常。 在过去的几十年中，早产的发生率已经上升，直到最近才稳定。这 最有影响力的治疗方法可防止早产（孕酮的孕产妇给药） 只有少数注定要过早交付的患者（即先前出生的患者或 缩短子宫颈），不能用于已经分娩的患者。本提案旨在利用 来自小鼠感染和炎症模型的发现，表现出强大的外源性抗Labor效应 施用的表面活性剂蛋白A（SP-A），一种由胎儿和母体组织产生的蛋白质。较新的数据 建议即使在系统地（即静脉注射）和小时内施用SP-A的情况下仍然存在这种效果 在实现劳动刺激后，对潜在临床使用很重要的区别。这 提案将解决研究SP-A以防止早产的三个目标：1）确定至关重要的 SP-A分子的结构域（即最小功能单位或MFU）的抗labor和抗抗 由于活细菌感染或无菌炎症态在劳动期间的炎症功能 老鼠; 2）评估SP-A MFU在小鼠及其后代的安全性； 3）检验了以下假设 SP-A的上述影响取决于收费受体（TLR）2及其下游信号的参与 转导机制。作为发育中胎儿产生的内源性蛋白，SP-A可能具有 出色的安全性。该项目将为开发SP-A作为预防性或 人类早产的治疗剂，从而提供了潜在的新机会 家庭和社会的发病率，苦难和成本早产。

项目成果

Toxic effects of trace phenol/guanidine isothiocyanate (P/GI) on cells cultured nearby in covered 96-well plates.

• DOI: 10.1186/s12896-022-00766-2
• 发表时间: 2022-11-25
• 期刊: BMC BIOTECHNOLOGY
• 影响因子: 3.5
• 作者: Snedden, Madeline;Singh, Lavisha;Kyathanahalli, Chandrashekara;Hirsch, Emmet
• 通讯作者: Hirsch, Emmet