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Epigenetic regulation of cell-autonomous type I interferon responses in trophoblast

滋养层细胞自主 I 型干扰素反应的表观遗传调控

基本信息

批准号：
MR/X008487/1
负责人：
Miguel Branco
金额：
$ 114.99万
依托单位：
Queen Mary University of London
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2023
资助国家：
英国
起止时间：
2023 至无数据
项目状态：
未结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FX008487%2F1
关键词：
Epigenetic regulation cell autonomous type

项目摘要

The placenta is an essential multi-functional organ that supports fetal development. Placental dysfunction has a major impact on both mother and fetus, and is associated with what are known as the great obstetrics syndromes, which include preeclampsia, intrauterine growth restriction and preterm birth. These in turn constitute risk factors for perinatal fetal mortality and morbidity, as well as long-term illness in adulthood. Yet the molecular underpinnings of placental dysfunction remain unclear, requiring research strategies that link basic mechanistic findings with phenotypes and clinical data.In this proposal we will focus on the regulation of inflammation in the placenta, and how it impacts pregnancy outcomes. Specifically, we will study the regulation of the type I interferon (IFN) response, which constitutes an innate immunity pathway against pathogens such as viruses and bacteria. Notably, type I IFN responses are involved in normal processes in pregnancy such as labour, which presumably occur in sterile conditions. Similarly, dysregulation of type I IFNs is linked to preterm birth, yet this can also seemingly occur in the absence of infection. This suggests that there are cell-intrinsic triggers of inflammation in the placenta.Indeed, we have found that trophoblast (cells of the placenta) can autonomously display a type I IFN response when cells are depleted of the KAP1 protein. KAP1 is an important accessory protein for epigenetic mechanisms that regulates not only the expression of genes, but also, and arguably most prominently, that of transposable elements (TEs). TEs are repetitive sequences that integrated and replicated within genomes, having expanded to make up approximately half of the human genome. TEs have played important roles in the evolution of the placenta. A key aspect of TE biology relevant to this proposal is that many are derived from ancient retroviruses and can mimic many of their actions, including triggering inflammatory responses within the cell. We therefore hypothesize that epigenetic deregulation of TEs can drive infection-independent type I IFN responses in the placenta, with potential impact for pregnancy outcomes. This is supported by preliminary data in cultured cells and human placentas.We propose to test this hypothesis by investigating molecular mechanisms in cultured cells, testing phenotypes in animal models, and finally analysing placental samples from appropriate human cohorts. In cell culture models we will deepen our findings on KAP1 and expand it to other TE-regulatory pathways. We will also directly test for a role of TEs in driving type I IFN responses. In mice, we will test the effect of KAP1 and TE deregulation on markers of inflammation, placental development and gestational timing. In humans, we will ask whether sterile type I IFN responses are associated with TE deregulation, both in term and preterm placentas. Through this comprehensive work programme we aim to uncover novel mechanistic and clinical insights into placental inflammation, and its links to normal and pathological pregnancy events.

胎盘是支持胎儿发育的重要多功能器官。胎盘功能障碍对母亲和胎儿都有重大影响，并与所谓的重大产科综合症有关，包括先兆子痫、宫内生长受限和早产。这些反过来又构成围产期胎儿死亡率和发病率以及成年期长期疾病的危险因素。然而，胎盘功能障碍的分子基础仍不清楚，需要将基本机制发现与表型和临床数据联系起来的研究策略。在本提案中，我们将重点关注胎盘炎症的调节及其如何影响妊娠结局。具体来说，我们将研究I型干扰素（IFN）反应的调节，它构成了针对病毒和细菌等病原体的先天免疫途径。值得注意的是，I 型干扰素反应涉及妊娠期的正常过程，例如分娩，这可能发生在无菌条件下。同样，I 型干扰素的失调与早产有关，但这种情况似乎也可能在没有感染的情况下发生。这表明胎盘中存在细胞内在的炎症触发因素。事实上，我们发现，当细胞中的 KAP1 蛋白耗尽时，滋养层（胎盘细胞）可以自主地表现出 I 型 IFN 反应。 KAP1 是表观遗传机制的重要辅助蛋白，它不仅调节基因的表达，而且可以说最重要的是调节转座元件 (TE) 的表达。 TE 是在基因组内整合和复制的重复序列，已扩展至约占人类基因组的一半。 TE 在胎盘的进化过程中发挥了重要作用。与该提议相关的 TE 生物学的一个关键方面是，许多都源自古老的逆转录病毒，并且可以模仿它们的许多行为，包括触发细胞内的炎症反应。因此，我们假设 TE 的表观遗传失调可以驱动胎盘中与感染无关的 I 型 IFN 反应，从而对妊娠结局产生潜在影响。这得到了培养细胞和人类胎盘的初步数据的支持。我们建议通过研究培养细胞的分子机制，测试动物模型的表型，最后分析来自适当人类群体的胎盘样本来检验这一假设。在细胞培养模型中，我们将深化对 KAP1 的发现，并将其扩展到其他 TE 调控途径。我们还将直接测试 TE 在驱动 I 型 IFN 反应中的作用。在小鼠中，我们将测试 KAP1 和 TE 失调对炎症标志物、胎盘发育和妊娠时间的影响。在人类中，我们将询问足月胎盘和早产胎盘中的无菌 I 型 IFN 反应是否与 TE 失调相关。通过这个全面的工作计划，我们的目标是揭示胎盘炎症的新机制和临床见解，及其与正常和病理性妊娠事件的联系。