Targeted Inhibition of Interleukin-1 beta to Prevent Preterm Birth

靶向抑制白细胞介素 1 β (IL-1 beta) 预防早产

基本信息

批准号：
10162632
负责人：
KRISTINA M. ADAMS WALDORF
金额：
$ 77万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-11 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10162632
关键词：
Acids Amino Acids Amniotic Fluid Anatomy Animal Model Animals Antibiotics Area Under Curve Bacteria Bacterial Infections Birth Brain Caring Catheters Cells Cesarean section Chorion Chorionic villi Chronic Clinical Continuous Infusion Cytokine Network Pathway Data Decidua Development Dose Drug Kinetics Escherichia coli FDA approved Fetal Lung Fetal safety Fetus Flow Cytometry Funding Gene Expression Half-Life Histopathology Hormonal Human IL1R1 gene Immune response Immunologics Implant Induced Labor Infection Inflammation Inflammation Mediators Inflammatory Inflammatory Infiltrate Injury Interleukin-1 Interleukin-1 Receptors Interleukin-1 beta Intervention Intravenous Bolus Kineret Letters Lipopolysaccharides Lung Mass Spectrum Analysis Maternal-Fetal Exchange Mediating Membrane Methods Modeling Molecular Target Mus Names Neonatal Mortality Outcome Pathway interactions Peptides Perinatal Perinatal mortality demographics Pharmaceutical Preparations Placenta Placentation Plasma Population Pregnancy Pregnant Women Premature Birth Premature Labor Prevention Prostaglandins Publishing Rattus Regulator Genes Research Safety Sampling Signal Transduction Specificity Sterility Streptococcal Infections Streptococcus Group B Testing Therapeutic Time Tissues Translations Treatment Efficacy Uterine Contraction Uterine Monitoring Uterus Vagina ZIKA adverse pregnancy outcome amnion amniotic cavity anakinra antenatal clinically significant cytokine digital effective therapy efficacy testing experimental study fetal fetal blood infant death inhibitor/antagonist intraamniotic infection microbial neonatal death neonatal morbidity neonatal sepsis neonate new technology nonhuman primate novel pathogen preclinical study pregnant prevent primary outcome protein expression reproductive secondary outcome single-cell RNA sequencing stillbirth therapeutic evaluation transcriptomics

项目摘要

PROJECT SUMMARY/ABSTRACT Preterm birth remains a significant cause of neonatal morbidity and mortality. Intra-amniotic infection and inflammation are important triggers for early preterm birth, which is associated with fetal injury mediated by cytokines and other inflammatory mediators in the amniotic fluid and fetus. The objective of this proposal is to establish the efficacy and safety of a novel selective allosteric interleukin-1 receptor (IL-1R) inhibitor (Rytvela) as an antenatal therapeutic strategy to prevent fetal injury and PTB. In pregnant mice, we have strong evidence that Rytvela is a potent suppressor of preterm birth and fetal injury induced by either lipopolysaccharide or lipotechoic acid. To enable translation of these discoveries to human pregnancy, we propose to test the efficacy and determine pharmacokinetics of Rytvela in a pregnant nonhuman primate model of preterm labor induced by Group B Streptococcus (GBS), a clinically important bacterium that colonizes the vagina and can cause preterm labor and neonatal sepsis. Our unique chronically catheterized nonhuman primate model has the greatest relevance to human pregnancy of any animal model and allows sampling in normally inaccessible compartments (amniotic fluid, maternal and fetal blood) multiple times without disrupting the pregnancy. New preliminary studies added to this resubmission demonstrate: 1) inhibition of preterm birth by Rytvela for at least 7 days (clinically significant endpoint), 2) determination of Rytvela pharmacokinetics in a rat model, 3) ability to quantify Rytvela using mass spectrometry in plasma for pharmacokinetics studies, and 3) incorporation of novel technology (Digital Spatial Profiling) to study immune responses at the maternal-fetal interface. In Aim 1, we will determine Rytvela pharmacokinetics in our NHP model and establish if IL-1 inhibition by Rytvela delays the onset of GBS-induced preterm labor. Aim 2 will determine if IL-1 inhibition by Rytvela can ameliorate inflammatory injury to the placenta, fetal lung and brain using three high-throughput multiplexed analyses: 1) multidimensional flow cytometry to quantitate cell populations, 2) Digital Spatial Profiling to interrogate immunologic protein expression and pathway activation in discrete tissues (amnion, chorion, decidua) of the placental chorioamniotic membranes, and 3) single cell RNA-Seq for transcriptomic profiling of regulatory gene networks within single cells in placental tissues. These experiments represent a natural progression of preliminary studies in multiple animal models and are essential to determining whether IL-1 is a viable molecular target for the prevention of preterm birth and fetal protection.

项目摘要/摘要早产仍然是新生儿发病率和死亡率的重要原因。肿瘤内感染和炎症是早产的重要触发因素，这与由胎儿损伤有关羊水和胎儿中的细胞因子和其他炎症介质。该提议的目的是建立新型选择性变构白素-1受体（IL-1R）抑制剂的功效和安全性（Rytvela）作为预防胎儿损伤和PTB的产前治疗策略。在怀孕的老鼠中，我们有有力的证据表明，瑞特维拉（Rytvela 脂多糖或脂肪酸。为了使这些发现转化为人类怀孕，我们提议测试功效并确定孕妇非人类灵长类动物模型中Rytvela的药代动力学 B组链球菌（GBS）诱导的早产，这是一种临床上重要的细菌，可将阴道，可能引起早产和新生儿败血症。我们独特的慢性导管非人类灵长类动物模型与任何动物模型的人类怀孕具有最大的相关性，并允许在正常情况下进行采样无法访问的隔室（羊水，母体和胎儿血）多次怀孕。在此重新提交中添加的新初步研究表明：1）通过 rytvela至少7天（临床上显着终点），2）大鼠rytvela药代动力学的测定模型，3）在药代动力学研究中使用质谱使用质谱来量化Rytvela的能力，3）将新技术（数字空间分析）纳入以研究母亲的免疫反应界面。在AIM 1中，我们将在NHP模型中确定Rytvela药代动力学并确定IL-1抑制作用是否 Rytvela延迟了GBS引起的早产劳动的发作。 AIM 2将确定Rytvela抑制IL-1是否可以使用三个高通量多路复用分析：1）定量细胞种群的多维流式细胞仪，2）数字空间分析到询问离散组织中的免疫学蛋白表达和途径激活（羊膜，绒毛膜，decidua）胎盘绒毛膜膜和3）单细胞RNA-seq用于调节的转录组学分析胎盘组织中单细胞内的基因网络。这些实验代表了自然发展在多种动物模型中的初步研究，对于确定IL-1是否是可行的分子至关重要预防早产和胎儿保护的目标。