Epigenetics of decidual inflammation

蜕膜炎症的表观遗传学

• 批准号: 10673396
• 负责人: Adrian Erlebacher
• 金额: $ 41.19万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10673396
• 关键词: Acute; Affect; Biopsy; Blood; Cells; Code; Conceptus; Decidua; Decidual Cell Reactions; Development; Disease; EZH2 gene; Endometrial; Endometrial Stromal Cell; Epigenetic Process; Etiology; Fibroblasts; First Pregnancy Trimester; Fostering; Gene Expression; Gene Silencing; Generations; Genes; Genetic; Histones; Human; Immune; Immune response; Immunologics; Impairment; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Knowledge; Laboratory Study; Leukocytes; Macrophage; Maternal-Fetal Exchange; Methylation; Methyltransferase; Modeling; Mus; Pathology; Pathway interactions; Patients; Peripheral; Phenotype; Placenta; Placentation; Play; Pregnancy; Pregnancy Outcome; Proteins; Protocols documentation; Reaction; Regulation; Regulatory Pathway; Role; Sampling; Specimen; Stromal Cells; T-Cell Activation; T-Lymphocyte; Techniques; Testing; Time; Tissues; Uterus; Woman; Work; early experience; early pregnancy; endometriosis; epigenetic silencing; experimental study; female fertility; genome-wide; genomic locus; histone modification; immunoreaction; implantation; imprint; in vivo; insight; mouse model; neutrophil; pregnancy failure; preimplantation; prevent; promoter; recruit; response; success; wound healing

The decidua is thought to play a central role in pregnancy by providing trophic and structural support for the placenta. In addition, recent work has indicated that it actively inhibits tissue reactions that, while normal for other tissues, would be problematic for pregnancy. One particularly important example is the suppression of acute inflammatory reactions, including ones that could recruit activated T cells from the blood. This proposal investigates the extent to which such suppression is due to the epigenetic silencing of inflammatory target genes in decidual stromal cells (DSCs). Specifically, we seek to gain insight into how repressive histone modifications generated in DSCs upon their differentiation from endometrial stromal cells (ESCs) prevent gene expression that would otherwise engender maladaptive inflammatory and immune reactions. Importantly, inflammation itself is known to regulate the generation and erasure of histone marks in a variety of non-uterine contexts, and once altered, the histone configuration of an affected gene locus can persist for extended periods of time. Thus, we will also test the hypothesis that pre-implantation uterine inflammation can affect post-implantation pregnancy outcomes in part by permanently altering the histone configurations of select gene loci in endometrial stromal cells. These configurations might be detrimental to early pregnancy to the extent they allow for maladaptive inflammatory reactions, but they also might be advantageous to the extent that they limit such reactions. In Aim 1, we will determine, in genome-wide fashion and in both mice and humans, how repressive histone mark (H2AK119Ub, H3K9me2 and H3K27me3) distributions change in ESCs upon decidualization. This Aim will assess ESCs from endometrial biopsies of non-pregnant women and DSCs from first trimester decidual specimens. The specimens will moreover come from normal women and women with endometriosis, thus providing insight into how endometrial inflammation influences mark generation in vivo. We will perform parallel studies in mice, inducing uterine inflammation in the pre-implantation period to determine its effects on histone mark generation in post-implantation DSCs. Aim 2 then utilizes genetic mouse models in order to functionally dissect the consequences of disrupted mark generation on the early decidua, including whether it now mounts overly robust immunological responses that might impair fetoplacental development. Lastly, Aim 3 will identify the mechanisms regulating the genome-wide distributions of repressive histone marks in primary human endometrial stromal fibroblasts induced to decidualize in vitro. This Aim will directly test the effects of pre-decidual inflammation, thus creating models to dissect the effects of endometrial inflammation uncovered in Aim 1. Together we expect our studies to provide insight into key regulatory circuitry that underpins the immunological quiescence of the first trimester decidua, and into how inflammatory endometrial pathology disrupts such circuitry to reduce female fertility.

蜕膜被认为通过提供营养和结构上的支持，在妊娠中发挥核心作用。 胎盘。此外，最近的研究表明，它能有效地抑制组织反应，尽管对 其他组织，将是怀孕的问题。一个特别重要的例子是对 急性炎症反应，包括可以从血液中招募激活的T细胞的反应。这项建议 调查这种抑制在多大程度上是由于炎症靶点的表观遗传沉默 蜕膜基质细胞中的基因。具体地说，我们试图深入了解抑制性组蛋白是如何 DSCs从子宫内膜间质细胞(ESCs)分化后产生的修饰可阻止基因 否则会导致不适应的炎症和免疫反应的表达。重要的是 已知炎症本身调节各种非子宫组织中组蛋白标记的产生和清除。 背景，一旦改变，受影响基因位点的组蛋白构型可以持续更长时间 一段时间。因此，我们还将检验植入前子宫炎症可以影响 植入后妊娠结局部分通过永久改变选择基因的组蛋白构型 子宫内膜间质细胞中的基因座。这些构型在一定程度上可能对早孕有害 它们允许不适应的炎症反应，但它们也可能在一定程度上有利于它们 限制这种反应。在目标1中，我们将以全基因组的方式以及在小鼠和人类身上确定如何 抑制性组蛋白标记(H3AK119Ub、H3K9me2和H3K27me3)在胚胎干细胞中的分布 蜕膜化。这一目标将评估来自非妊娠妇女子宫内膜活检的ESCs和来自 早孕蜕膜标本。此外，样本还将来自正常女性和患有 子宫内膜异位症，从而提供对子宫内膜炎症如何影响体内标记生成的洞察。我们 将在小鼠身上进行平行研究，在植入前引发子宫炎症来确定 其对植入后DSCs组蛋白标记物生成的影响。然后，AIM 2利用遗传小鼠模型在 以便从功能上剖析印记生成中断对早期蜕膜的影响，包括 它现在是否会产生过度强大的免疫反应，可能会损害胎儿-胎盘的发育。 最后，目标3将确定抑制性组蛋白在全基因组分布的调控机制 体外诱导人子宫内膜间质成纤维细胞蜕膜分化的标志物。这一目标将直接 测试蜕膜前炎症的影响，从而建立模型来剖析子宫内膜的影响 炎症在AIM 1中被发现。我们希望我们的研究能够为关键的调控回路提供洞察力 这支持了早孕蜕膜的免疫学平静，以及如何产生炎症 子宫内膜病变破坏了这种循环，从而降低了女性的生育力。