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.

蜕膜被认为在妊娠中起核心作用，为妊娠提供营养和结构支持。 胎盘此外，最近的研究表明，它积极抑制组织反应，而正常的 其他组织，对怀孕来说是有问题的。一个特别重要的例子是， 急性炎症反应，包括那些可以从血液中招募激活的T细胞的反应。这项建议 研究了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（DSCs）中的基因。具体来说，我们试图深入了解抑制性组蛋白 DSCs从子宫内膜间质细胞（ESC）分化后产生的修饰阻止了基因表达。 表达，否则会产生适应不良的炎症和免疫反应。重要的是， 已知炎症本身调节各种非子宫内膜组织中组蛋白标记的产生和消除， 一旦改变，受影响基因位点的组蛋白构型可以持续很长时间。 一段时间。因此，我们也将测试这一假设，即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位点。这些配置可能对早孕有害， 它们允许适应不良的炎症反应，但它们也可能是有利的， 限制这种反应。在目标1中，我们将以全基因组的方式，在小鼠和人类中， 抑制性组蛋白标记（H2AK119Ub、H3K9me2和H3K27me3）在ESCs中的分布变化， 蜕膜化该目的将评估来自非妊娠妇女子宫内膜活检的ESC和来自非妊娠妇女子宫内膜活检的DSCs。 妊娠早期蜕膜标本。此外，样本将来自正常女性和患有 子宫内膜异位症，从而提供洞察子宫内膜炎症如何影响体内标记生成。我们 将在小鼠中进行平行研究，在植入前期诱导子宫炎症，以确定 其对植入后DSCs中组蛋白标记物生成的影响。Aim 2然后利用遗传小鼠模型， 为了从功能上剖析早期蜕膜上标记产生中断的后果，包括 它是否会引起可能损害胎儿胎盘发育的过度强烈的免疫反应。 最后，目标3将确定抑制性组蛋白在全基因组分布的调节机制 标记原代人子宫内膜间质成纤维细胞诱导体外蜕膜化。这一目标将直接 测试蜕膜前炎症的影响，从而建立模型来解剖子宫内膜的影响， 目标1中发现炎症。我们希望我们的研究能够为关键的调节电路提供深入的了解 这是前三个月蜕膜免疫静止的基础， 子宫内膜病变破坏了这种回路，从而降低了女性生育能力。