Innate Immune Mechanisms at the Maternal-Fetal Interface in Normal and Superovulatory Pregnancy

正常和超排卵妊娠母胎界面的先天免疫机制

• 批准号: 10447103
• 负责人: Aimee Melissa Beaulieu
• 金额: $ 76.67万
• 依托单位: RUTGERS BIOMEDICAL AND HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-21 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10447103
• 关键词: Area; Birth; Blood Vessels; Cell physiology; Cells; Child; Data; Decidual Cell Reactions; Development; Diagnostic; Disease; Early Diagnosis; Emotional; Endometrial; Epithelial; Epithelial Cells; Event; Family; Fertilization in Vitro; Fetal Growth; Fetal Growth Retardation; Financial cost; Foundations; Functional disorder; Habitual Abortion; Health; Heterogeneity; Human; Immune; Immune System Diseases; Immune response; Impairment; In Vitro; Inflammatory Response; Interferon Type II; Interleukin-1; Knockout Mice; Lead; Link; Low Birth Weight Infant; Macrophage Activation; Maternal-Fetal Exchange; Mediating; Molecular; Mothers; Mus; Natural Killer Cells; Neonatal; Outcome; Ovarian; Ovarian Stimulations; Placenta; Placental Insufficiency; Placentation; Play; Population; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Pregnancy loss; Prevention; Process; Production; Protocols documentation; Public Health; Recurrence; Risk; Role; Sampling; Signal Transduction; Superovulation; Testing; Therapeutic; Tissues; Uterus; Vascular Endothelial Growth Factors; Vascularization; Woman; angiogenesis; cost; cytokine; early pregnancy; fetal; fetal loss; healthy pregnancy; immune function; implantation; improved; in vivo; innate immune mechanisms; macrophage; mouse model; natural Blastocyst Implantation; placental morphology; pleiotropism; pregnancy disorder; pregnant; receptor; tool development

Project Summary/Abstract Placental insufficiency underlies many pregnancy disorders, including preeclampsia (PE), intrauterine growth restriction (IUGR) and recurrent pregnancy loss (RPL). Collectively, these disorders have costly, widespread, and sometimes long term, health consequences for the mother and/or child. Immune cell populations at the maternal-fetal interface, including uterine natural killer cells (uNKs) and uterine macrophages (uMacs), mediate angiogenesis and other key events in decidualization, placentation, and progression of pregnancy. Dysregulated inflammatory responses during decidualization or placentation have been linked to PE, IUGR, and RPL. Moreover, a growing number of births in the US are achieved using controlled ovarian stimulation (“superovulation”) protocols for in vitro fertilization (IVF), which is associated with dysregulated uterine immune cell function and increased risk of pregnancy complications due to placental dysfunction. The molecular mechanisms that regulate immune cell function at the maternal-fetal interface are poorly understood. Recent studies have highlighted critical roles for the IL-1 family cytokine, IL-33, in pregnancy, and aberrant maternal IL-33 signaling has been linked to RPL and PE in humans. Our preliminary data reveal numerous IL-33-expressing cells, including many IL-33+ uterine epithlelial cells, in the murine uterus at key stages of pregnancy. These IL-33+ cells are located in immune cell-rich regions heavily populated by uNKs and uMacs. Although IL-33 regulates key aspects of NK and Mac function in other tissues, its specific effects on uNKs and uMacs remains poorly understood. We hypothesize that IL-33 signaling supports decidualization and placentation by promoting uNK and uMac-mediated angiogenesis and tissue remodeling during pregnancy. Guided by this hypothesis, our proposed studies aim to: (1) Define the role of IL-33 signaling in pregnancy progression. We will utilize mice that lack IL-33 globally or in uterine epithelial cells, or mice in which IL-33 is neutralized at key stages of gestation, to define the role of IL-33 in decidualization, placental formation and placental function during pregnancy. (2) Determine the effects of IL-33 signaling on NK and Mac function at the maternal-fetal interface. We will use complementary in vitro approaches and in vivo studies in IL-33-deficient mice to determine how IL-33 signaling regulates the angiogenic and tissue remodeling activities of uNKs and uMacs during pregnancy. (3) Determine the impact of superovulation (SO) on uNK and uMac function. We will use mouse models of SO, in combination with studies on primary human endometrial samples from women undergoing SO for IVF, to investigate the impact of SO on IL-33-dependent and –independent uNK and uMac effector functions.

项目总结/摘要 胎盘功能不全是许多妊娠疾病的基础，包括先兆子痫（PE）、宫内生长 限制（IUGR）和复发性妊娠丢失（RPL）。总的来说，这些疾病具有昂贵的，广泛的， 有时会对母亲和/或孩子造成长期的健康后果。免疫细胞群在 母胎界面，包括子宫自然杀伤细胞（uNK）和子宫巨噬细胞（uMacs），介导 血管生成和蜕膜化、胎盘形成和妊娠进展中的其他关键事件。 在蜕膜化或胎盘形成过程中失调的炎症反应与PE、IUGR， 和RPL。此外，在美国，越来越多的分娩是通过控制性卵巢刺激实现的 体外受精（IVF）的超排卵（“超排卵”）方案，其与子宫免疫调节失调有关。 细胞功能和由于胎盘功能障碍导致的妊娠并发症风险增加。 在母胎界面调节免疫细胞功能的分子机制很差， 明白最近的研究强调了IL-1家族细胞因子IL-33在妊娠中的关键作用， 异常的母体IL-33信号传导与人类的RPL和PE有关。我们的初步数据显示 小鼠子宫中大量表达IL-33的细胞，包括许多IL-33+子宫上皮细胞， 怀孕的各个阶段。这些IL-33+细胞位于uNK大量聚集的富含免疫细胞的区域 uMacs。虽然IL-33调节其他组织中NK和Mac功能的关键方面，但其特异性作用 对uNK和uMac的了解仍然很少。我们假设IL-33信号支持蜕膜化 胎盘形成过程中促进uNK和uMac介导的血管生成和组织重塑 怀孕在这一假设的指导下，我们提出的研究旨在： (1)确定IL-33信号在妊娠进展中的作用。我们将在全球范围内使用缺乏IL-33的小鼠， 或子宫上皮细胞，或IL-33在妊娠关键阶段被中和的小鼠中，以确定IL-33的作用。 IL-33在妊娠期间蜕膜化、胎盘形成和胎盘功能中的作用 (2)确定IL-33信号传导对母胎界面NK和Mac功能的影响。我们 将使用互补的体外方法和IL-33缺陷小鼠的体内研究来确定IL-33 信号传导调节妊娠期间uNK和uMAC的血管生成和组织重塑活性。 (3)测定超数排卵（SO）对uNK和uMac功能的影响。我们将使用小鼠模型 结合对接受SO的女性的原发性人类子宫内膜样本的研究， 体外受精，以研究SO对IL-33依赖性和非依赖性uNK和uMac效应器功能的影响。