Anti-inflammatory drug target to reduce adverse pregnancy outcomes.

抗炎药物的目标是减少不良妊娠结局。

基本信息

批准号：
10618171
负责人：
SUHAS KALLAPUR
金额：
$ 69.37万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
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：
2019-06-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10618171
关键词：
Adverse event Amniotic Fluid Animal Model Animals Anti-Inflammatory Agents Antibiotics Bacteremia Biological Products Brain Cell Count Cells Classification Clinical Clinical Trials Complex Controlled Study Data Dinoprostone Discipline of obstetrics Disease Drug Targeting E. coli bacteremia Encephalitis Escherichia coli Fetal Lung Fetal Membranes Fetal Reduction Fetal Spleen Fetus Flow Cytometry Future Gastrointestinal tract structure Genes Genomics Grant Human Human Pathology IL6 gene Immune Immunologics Immunology Infectious Agent Inflammation Inflammation Mediators Inflammatory Injections Injury Interleukin-1 Interleukin-1 Receptors Knowledge Licensing Lung Lymphoid Cell Macaca mulatta Maternal and Child Health Maternal-Fetal Exchange Microglia Modeling Molecular Mucous Membrane NIH Program Announcements Neurosciences Neutrophil Activation Neutrophil Infiltration Organ Pathway interactions Peripheral Pharmaceutical Preparations Phenotype Placenta Population Positioning Attribute Preclinical Testing Pregnancy Pregnant Women Premature Birth Premature Labor Preparation Proteomics Public Health Publications Pulmonary Inflammation Recombinants Regulation Regulatory T-Lymphocyte Residual state Resolution Rhesus Rheumatoid Arthritis Route Signal Transduction Spleen Sterility Testing Therapeutic Thymus Gland Uterus adverse pregnancy outcome anakinra antagonist biomarker discovery cytokine drug development drug repurposing efficacy evaluation efficacy study experimental study fetal fetal brain injury improved inhibitor intrauterine infection intrauterine inflammation knowledge base multidisciplinary neonatal outcome neuroinflammation novel novel drug class novel marker novel therapeutics perinatal brain pharmacokinetics and pharmacodynamics pregnant premature prenatal prevent response to injury side effect single-cell RNA sequencing systemic inflammatory response transcriptomics translational approach

项目摘要

Abstract Intrauterine infection/inflammation (IUI) is a major contributor to preterm labor and fetal inflammation leading to injury responses in fetal organs such as the brain, lung and the GI tract. However, the mechanisms and precise therapeutic approaches remain elusive largely because of lack of relevant animal models. We have developed a powerful new model of intrauterine infection in preterm Rhesus macaques: Intraamniotic (IA) injection of live E. coli followed 24h later with antibiotics. This model results in persistent IUI. Importantly, the maternal and fetal inflammation persists despite clearance of E. coli bacteremia, resulting in preterm labor (PTL), fetal immune aberrations and fetal neuroinflammation. We now propose validating IL1 as a drug target for IUI induced prematurity and fetal inflammation. This grant is based on our data that Anakinra (IL1 receptor antagonist used clinically for rheumatoid arthritis) significantly decreased neutrophilic infiltration at the maternal-fetal interface and amniotic fluid IL6, PGE2 in a different but widely used model of IA LPS. Furthermore, Anakinra reversed the LPS-induced “inflammatory Treg” in the fetal spleen. We propose to test the hypothesis that Anakinra will reduce the residual maternal and fetal inflammation in infectious models that closely simulate IUI in pregnant women with two Aims. In Aim 1, we will ask if anti IL1 directed anti- inflammatory therapy will decrease intrauterine infection induced inflammation and preterm labor. We will use state-of-the-art single-cell transcriptomic approach to unravel cellular and molecular mechanisms of inflammation at the maternal-fetal interface, define labor associated pathways of IUI that are responsive to IL1 inhibition. Using multi-parameter flow cytometry, we will identify mechanisms of neutrophil recruitment and activation in the chorio-decidua. In Aim 2, We will identify mucosal and systemic fetal immune perturbations resulting from transient bacteremia and sterile fetal inflammation. We will determine if Anakinra can reduce fetal systemic inflammation and neuroinflammation resulting from IUI. These studies will develop the critical knowledge base for future studies aimed at repurposing of Anakinra as a novel anti-inflammatory therapy for human IUI. A collaborative multi-disciplinary team will use high-resolution immunology, genomics/proteomics, neuro-science, and translational approaches in modeling IUI and fetal inflammation in an animal model that closely mimics the human pathology.

抽象的插入感染/炎症（IUI）是早产和胎儿感染的主要因素，导致胎儿器官（例如大脑，肺和胃肠道）的损伤反应。但是，机制和精确的治疗方法仍然难以捉摸，这在很大程度上是由于缺乏相关的动物模型。我们有在早产恒河猕猴中开发了一种强大的新模型的新模型：羊膜内（IA）注射活的大肠杆菌随后24小时，使用抗生素。该模型导致持续的IUI。重要的是，孕产妇和胎儿炎症持续存在大肠杆菌细菌的目的地清除，导致早产（PTL），胎儿免疫像差和胎儿神经炎症。现在，我们建议将IL1验证为药物靶标对于IUI诱导的早产和胎儿注射。这笔赠款基于我们的数据，即Anakinra（IL1接收器）拮抗剂在临床上用于类风湿关节炎）显着改善了嗜中性粒细胞的浸润孕妇界面和羊水IL6，PGE2，以不同但广泛使用的IA LPS模型。此外，Anakinra逆转了胎儿臂中LPS引起的“炎症性Treg”。我们建议测试在感染模型中，Anakinra将减少残留的母体和胎儿感染的假设在有两个目标的孕妇中密切模拟IUI。在AIM 1中，我们将询问抗IL1是否指示抗抗炎症疗法将减少雷内感染引起的炎症和早产。我们将使用最先进的单细胞转录组方法，用于解开细胞和分子机制在母亲界面处的炎症，定义了对IL1响应的IUI的劳动相关途径抑制。使用多参数流式细胞仪，我们将确定中性粒细胞募集机制和在合唱 - decidua中激活。在AIM 2中，我们将确定粘膜和全身性胎儿免疫扰动瞬时细菌和无菌胎儿炎症。我们将确定Anakinra是否可以减少 IUI引起的胎儿全身炎症和神经炎症。这些研究将发展关键未来研究的知识库旨在将Anakinra作为一种新型的抗炎疗法重新利用人IUI。一个协作的多学科团队将使用高分辨率免疫学，基因组学/蛋白质组学，神经科学以及在动物模型中建模IUI和胎儿注射的转化方法密切模仿人类病理。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Studying the Effects of Granulocyte-Macrophage Colony-Stimulating Factor on Fetal Lung Macrophages During the Perinatal Period Using the Mouse Model.

DOI：
10.3389/fped.2021.614209
发表时间：
2021
期刊：
Frontiers in pediatrics
影响因子：
2.6
作者：
Cheah FC;Presicce P;Tan TL;Carey BC;Kallapur SG
通讯作者：
Kallapur SG

BAFF and APRIL counterregulate susceptibility to inflammation-induced preterm birth.

DOI：
10.1016/j.celrep.2023.112352
发表时间：
2023-04-25
期刊：
Cell reports
影响因子：
8.8
作者：
通讯作者：

Characterization of methylation profiles in spontaneous preterm birth placental villous tissue.

DOI：
10.1371/journal.pone.0279991
发表时间：
2023
期刊：
PLOS ONE
影响因子：
3.7
作者：
Brockway, Heather M.;Wilson, Samantha L.;Kallapur, Suhas G.;Buhimschi, Catalin S.;Muglia, Louis J.;Jones, Helen N.
通讯作者：
Jones, Helen N.