Effect of fetal exposure to maternal inflammation on offspring Paneth cell development and homeostasis

胎儿暴露于母体炎症对后代潘氏细胞发育和稳态的影响

• 批准号: 10295982
• 负责人: Steven James McElroy
• 金额: $ 51.49万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10295982
• 关键词: Acute; Address; Bacteria; Bacterial Infections; Beds; Biology; Cell Density; Cell Differentiation process; Cell physiology; Cellular Morphology; Cellular biology; Cessation of life; Chronic; Critical Pathways; Data; Development; Event; Exposure to; Family; Fetus; Functional disorder; Genetic; Goals; Growth and Development function; Health; Homeostasis; Human; Impairment; In Vitro; Infant; Inflammation; Inflammatory; Injury; Interferons; Interleukin-6; Intervention; Intestines; Investigation; Knockout Mice; Knowledge; Lead; Medical; Mission; Modeling; Morbidity - disease rate; Mus; Necrotizing Enterocolitis; Neonatal Mortality; Normal tissue morphology; Organoids; Outcome; Paneth Cells; Pathogenesis; Pathogenicity; Pathologic; Pathology; Pathway interactions; Placenta; Predisposition; Pregnancy; Premature Birth; Premature Infant; Premature Mortality; Prevention strategy; Process; Production; Public Health; Publishing; Quality of life; Research; Risk; Role; STAT1 protein; STAT3 gene; Secondary to; Secretory Cell; Serum; Signal Pathway; Signal Transduction; Site; Source; Sterility; Techniques; Testing; Tissues; United States National Institutes of Health; adverse outcome; body system; clinically relevant; conditional knockout; cytokine; density; experimental study; fetal; improved; in vivo; innovation; intestinal epithelium; intestinal injury; intraamniotic infection; neonatal morbidity; novel; offspring; prenatal exposure; prevent; recruit; restoration; targeted treatment; tissue injury; transcription factor

Chorioamnionitis complicates up to 70% of preterm births, and is characterized by acute inflammation of the placental/fetal unit, exposing the fetus to significant inflammation. These infants have an increased risk of short- and long-term morbidities involving multiple organ systems including the intestine. However, mechanisms by which fetal exposure to maternal inflammation (FEMI) leads to adverse outcomes remain unclear. Our preliminary and published data show that an interleukin-6 (IL-6)-dependent loss of Paneth cells contributes to FEMI-associated susceptibility to bowel injury. Our data suggest that FEMI leads to: IL-6- dependent Paneth cell loss; lingering elevation of serum baseline levels of inflammatory cytokines, including IL-6; clinically relevant intestinal injury; and increased susceptibility to secondary intestinal injury. However, specific mechanisms underlying these effects including the source of IL-6, the site of IL-6-induced pathogenic action, specific signal pathways by which Paneth cells are impacted, and subsequent consequences of Paneth cell perturbation remain incompletely understood. Addressing this gap in knowledge is critical for restoring IL-6 modulation, a potential interventional opportunity for preventing FEMI-induced pathology. The objective of this proposal is to delineate key mechanisms by which FEMI decreases Paneth cells and increases susceptibility to intestinal injury in the offspring. Our central hypothesis is that fetal exposure to IL-6 from maternal or placental (or both) sources is a key mechanism by which FEMI alters signal transducers and activators of transcription-1 signaling in the offspring, leading to increased interferon lambda signal pathways, reduced Paneth cell density, and increased injury susceptibility. The rationale for undertaking this project is to gain a mechanistic advance in knowledge of how FEMI leads to neonatal morbidity and mortality. Such knowledge will be critical to develop novel preventative strategies, to prevent complications and mortality of prematurity, and to directly improve the quality of life of pre-term infants. Our hypothesis will be tested through two aims: 1) Identify the site(s) of pathologic action of IL-6 and downstream signaling pathways activated following FEMI, and 2) Determine the effects of FEMI on pathways critical to Paneth cell homeostasis. The proposed research is significant and innovative as our proposed studies will directly address the gap in knowledge regarding increased neonatal morbidity and mortality following FEMI and specifically the impact on Paneth cells using novel in vivo, in vitro, and ex vivo approaches to investigate the role of FEMI-induced IL-6 on fetal outcomes. This knowledge will lead to development of targeted therapies to improve intestinal health.

绒毛膜炎使高达70%的早产并发症，其特征在于绒毛膜炎的急性炎症。 胎盘/胎儿单位，使胎儿暴露于显著炎症。这些婴儿有增加的风险 涉及包括肠道在内的多个器官系统的短期和长期发病率。然而，在这方面， 胎儿暴露于母体炎症（FEMI）导致不良结局的机制仍然存在 不清楚我们的初步和已发表的数据表明，白细胞介素-6（IL-6）依赖性潘氏细胞损失 导致FEMI相关的肠损伤易感性。我们的数据表明，FEMI导致：IL-6- 依赖性潘氏细胞损失;炎性细胞因子的血清基线水平持续升高，包括 IL-6;临床相关的肠损伤;和继发性肠损伤易感性增加。然而，在这方面， 这些作用的具体机制包括IL-6的来源，IL-6诱导的致病性的位点， 作用，影响潘氏细胞的特定信号通路，以及潘氏细胞的后续后果 细胞扰动仍然不完全理解。解决这一知识差距对于恢复IL-6至关重要 调制，一个潜在的干预机会，以防止FEMI诱导的病理。的目的 一项新的建议是描述FEMI减少潘氏细胞和增加对 后代的肠道损伤。我们的中心假设是胎儿暴露于母体或胎盘IL-6， (or两者）来源是FEMI改变信号转导和转录激活因子-1的关键机制 后代中的信号传导，导致干扰素λ信号途径增加，潘氏细胞密度降低， 和增加的损伤敏感性。进行这个项目的基本原理是获得一个机械的进步 了解FEMI如何导致新生儿发病率和死亡率。这些知识对于开发 新的预防策略，以防止并发症和早产死亡率，并直接改善 早产儿的生活质量。我们的假设将通过两个目标进行检验：1）确定 IL-6和下游信号通路在FEMI后激活的病理作用，和2）确定 FEMI对潘氏细胞稳态关键途径的影响。这项研究意义重大， 创新，因为我们提出的研究将直接解决有关新生儿增加的知识差距差距， FEMI后的发病率和死亡率，特别是使用新的体内，体外， 和离体方法来研究FEMI诱导的IL-6对胎儿结局的作用。这些知识将 从而开发出改善肠道健康的靶向疗法。