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.

抽象的宫内感染/炎症 (IUI) 是早产和胎儿炎症的主要原因然而，胎儿器官如脑、肺和胃肠道的损伤反应，其机制和机制尚不清楚。精确的治疗方法仍然难以捉摸，很大程度上是因为我们缺乏相关的动物模型。开发了一种强大的早产恒河猴宫内感染新模型：羊膜内（IA） 24 小时后注射活大肠杆菌，该模型导致持续的 IUI。尽管大肠杆菌菌血症被清除，母体和胎儿的炎症仍然存在，导致早产 (PTL)、胎儿免疫畸变和胎儿神经炎症我们现在建议验证 IL1 作为药物靶点。用于 IUI 引起的早产和胎儿炎症。这笔资助是基于我们的 Anakinra（IL1 受体）数据。临床上用于治疗类风湿性关节炎的拮抗剂）显着减少了中性粒细胞浸润在不同但广泛使用的 IA LPS 模型中观察母胎界面和羊水 IL6、PGE2。此外，Anakinra 逆转了胎儿脾脏中 LPS 诱导的“炎症 Treg”。阿纳白滞素将减少感染模型中残留的母体和胎儿炎症的假设密切模拟孕妇的 IUI，有两个目标在目标 1 中，我们将询问抗 IL1 是否直接抗。炎症治疗将减少宫内感染引起的炎症和早产。最先进的单细胞转录组学方法来揭示细胞和分子机制母胎界面的炎症，定义对 IL1 敏感的 IUI 分娩相关途径使用多参数流式细胞术，我们将确定中性粒细胞募集和抑制的机制。在目标 2 中，我们将识别粘膜和全身胎儿免疫扰动。我们将确定阿那白滞素是否可以减少由短暂性菌血症和无菌胎儿炎症引起的感染。这些研究将揭示 IUI 引起的胎儿全身炎症和神经炎症的关键。未来研究的知识库，旨在重新利用阿那白滞素作为一种新型抗炎疗法人类 IUI。多学科协作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模拟 IUI 和胎儿炎症的转化方法密切模仿人类病理学。

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.