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.

据认为，Decidua通过为妊娠中扮演着核心角色，通过为 胎盘。此外，最近的工作表明，它积极抑制组织反应，虽然是正常的 其他组织，怀孕将是有问题的。一个特别重要的例子是压制 急性炎症反应，包括可以从血液中募集活化的T细胞的反应。这个建议 研究这种抑制是由于炎症靶标的表观遗传沉默而导致的程度 决结质细胞（DSC）中的基因。具体来说，我们试图深入了解抑制性组蛋白 DSC与子宫内膜基质细胞（ESC）在DSC中产生的修饰预防基因 表达否则会引起适应不良的炎症和免疫反应。重要的是， 众所周知，炎症本身会调节各种非独特氨酸中组蛋白标记的产生和擦除 上下文，一旦改变，受影响基因座的组蛋白配置可以持续到扩展 一段时间。因此，我们还将检验以下假设：植入前子宫炎症会影响 植入后妊娠结局部分是通过永久改变精选基因的组蛋白构型的部分 子宫内膜基质细胞中的基因座。这些配置可能在范围内对早期怀孕有害 它们允许适应不良的炎症反应，但它们在某种程度上也可能是有利的 限制此类反应。在AIM 1中，我们将以全基因组的方式以及在小鼠和人类中确定如何确定 抑制性组蛋白标记（H2AK119UB，H3K9ME2和H3K27ME3）分布在ESC上发生变化 十字无限。这个目标将评估非怀孕妇女的子宫内膜活检和DSC的ESC 头三个月的标本。此外，标本将来自普通妇女和妇女 子宫内膜异位症，因此提供了有关子宫内膜炎症如何影响体内产生的洞察力。我们 将在小鼠中进行平行研究，在植入前诱导子宫炎症以确定 它对植入后DSC中组蛋白标记产生的影响。 AIM 2然后利用遗传小鼠模型 为了在功能上剖析decidua早期标记产生的后果，包括 现在，它是否具有过度强大的免疫反应，可能会损害胎儿的发展。 最后，AIM 3将确定调节抑制性组蛋白基因组分布的机制 原发性人子宫内膜基质成纤维细胞的标记诱导在体外降解。这个目标将直接 测试前期炎症的影响，从而创建模型以剖析子宫内膜的影响 在AIM 1中发现了炎症。我们期望我们的研究能够深入了解关键调节电路 这支撑了头三个月的免疫学静止以及炎症的方式 子宫内膜病理破坏了这种回路以降低女性的生育能力。