Placenta-specific miR-519c-mediated induction of immune tolerance in human placenta

胎盘特异性 miR-519c 介导的人胎盘免疫耐受诱导

• 批准号: 10611511
• 负责人: Nazeeh N Hanna
• 金额: $ 32.45万
• 依托单位: NYU LONG ISLAND SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-02 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10611511
• 关键词: Address; Anti-Inflammatory Agents; Attenuated; Bacterial Toxins; Biological Markers; Cells; Clinical; Data; Disease; Distant; Dose; Down-Regulation; Endometrial; Environment; Equilibrium; Exhibits; Exposure to; Fetus; Future; Grant; Histologic; Host Defense; Human; Immune; Immune Tolerance; Immune response; Immune system; Immunosuppression; Infection; Inflammation; Inflammatory; Inflammatory Response; Invaded; Link; Maintenance; Maternal-Fetal Exchange; Mediating; MicroRNAs; Microbe; Modeling; Molecular; Mothers; Mus; Organism; Pathologic; Phenotype; Placenta; Placentation; Play; Pregnancy; Pregnancy Trimesters; Pregnant Women; Premature Birth; Production; Research; Role; Signal Transduction; Stimulus; Testing; Therapeutic; Tissues; Uterine Contraction; Woman; biomarker identification; candidate marker; cell type; experimental study; extracellular vesicles; fetal; healthy pregnancy; human disease; implantation; intraamniotic infection; intrauterine environment; mortality; novel; pathogen; pathogenic microbe; prevent; therapeutic target; tissue injury; trophoblast

SUMMARY/ABSTRACT Pregnancy represents a unique challenge for the maternal-fetal immune interface, requiring the balance between immunosuppression, essential for the maintenance of semi-allogeneic fetus and pro-inflammatory host defense to protect the mother and fetus from invading organisms. Adaptation to repeated inflammatory stimuli may be critical in preventing rejection of the fetus by the exaggerated maternal inflammatory responses to mild/moderate infections that are common during human pregnancy. Immune tolerance/adaptation is a well-described phenomenon in which cells exposed to repeated pathogens become less responsive to subsequent exposures. This adaptation suppresses an overly aggressive inflammatory response to repeated infections that can be detrimental to the tissues rather than protective. Dampened immune response to repeated infections has been associated with protection against tissue injury and mortality in several human diseases. However, to date, the role of immune tolerance to repeated infections in the context of human pregnancy, and the exact mechanisms that contribute to the establishment of such immune adaptation to prevent inflammation-induced pathologic pregnancies are not explored. There is now extensive evidence that miRNAs play an important role in the maintenance of a healthy pregnancy, with a wide range of miRNAs implicated in endometrial receptivity, implantation, gestational tissues function, and labor. Our preliminary results indicate that repeated LPS (gram negative bacterial toxins) or LTA (gram-positive bacterial toxins) exposures to human placenta attenuates exaggerated inflammatory responses known to contribute to inflammation-associated pathologic pregnancies. Our data also point to the involvement of a human- and placenta-specific miRNA called miRNA-519c-3p (miR-519c) in the development of placental immune tolerance. Our overriding hypothesis is that repeated exposure of the placenta to pathogens induces a tolerant phenotype mediated by the miR-519c to guard the maternal-fetal interface from the exaggerated inflammation associated with pathologic pregnancies. We hypothesize that LPS/LTA induce placental trophoblasts to secrete miR-519c packaged within placental extracellular vesicles for delivery to nearby or distant cells. The miR-519c within the EVs will mediate down-regulation of exaggerated pro-inflammatory responses associated with repeated bacterial toxin exposures. We propose the following specific aims: Aim 1: Investigate the role of miR-519c in mediating immune adaptation in the human placenta after repeated infections and Aim 2: Investigate the molecular mechanisms of placental miR-519c mediating immune adaptation. These studies will set the stage for future experiments to test if decreased expression of miR-519c is linked to inflammation-associated pathologic pregnancies. This unique human- and placenta-specific miR-519c can be an excellent biomarker candidate as well as a therapeutic target for inflammatory diseases of pregnancy.

摘要/摘要 怀孕代表了母亲 - 狂热界面的独特挑战，需要平衡 在免疫抑制之间，对于维持半化合物胎儿和促炎症至关重要 主持人防御以保护母亲和胎儿免受入侵生物的侵害。适应反复炎症 刺激对于防止夸张的母体炎症反应对胎儿排斥至关重要 在人类怀孕期间常见的轻度/中度感染。 免疫耐受性/适应性是一种很好的现象，其中细胞暴露于重复 病原体对随后的暴露反应较少。这种适应会抑制过度 对反复感染的侵略性炎症反应可能对组织有害而不是 保护的。对重复感染的免疫反应抑制与保护有关 几种人类疾病的组织损伤和死亡率。但是，迄今为止，免疫耐受性的作用 在人类怀孕的背景下重复感染，以及有助于促成的确切机制 建立这种免疫适应以防止炎症引起的病理妊娠不是 探索。现在有大量证据表明，miRNA在维持健康中起着重要作用 怀孕，涉及子宫内膜接受，植入和妊娠组织的广泛miRNA 功能和劳动。我们的初步结果表明重复的LP（革兰氏阴性细菌毒素）或LTA （革兰氏阳性细菌毒素）暴露于人体胎盘的暴露减弱了夸张的炎症反应 已知会导致与炎症相关的病理妊娠。我们的数据也指向参与 胎盘发育中的人类和胎盘特异性miRNA称为miRNA-519C-3P（miR-519c） 免疫耐受性。我们的压倒性假设是，胎盘反复暴露于病原体会诱导A 由miR-519c介导的耐受表型，以防止夸张的母亲界面 与病理妊娠有关的炎症。我们假设LPS/LTA诱导胎盘 滋养细胞分泌胎盘外囊泡中包装的miR-519c，以送到附近或 远处的细胞。电动汽车内的miR-519c将介导夸张的促炎性炎症的下调 与重复的细菌毒素暴露有关的反应。 我们提出以下特定目的：目标1：研究miR-519c在介导免疫中的作用 反复感染后，人胎盘的适应和目标2：研究分子机制 胎盘miR-519c介导免疫适应。这些研究将为将来的实验奠定阶段 测试如果miR-519c的表达降低与炎症相关的病理妊娠有关。这 独特的人类和胎盘特异性miR-519c可以是出色的生物标志物候选者 怀孕炎症疾病的治疗靶标。