Understanding the role of KDM6B in parturition onset

了解 KDM6B 在分娩开始中的作用

• 批准号: 10597037
• 负责人: Tara Mcintyre
• 金额: $ 3.99万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10597037
• 关键词: Age; Biology; Birth; Cause of Death; Child; Coculture Techniques; Complex; Data; Developed Countries; Endometrium; Engineering; Enzymes; Epigenetic Process; Epithelial Cells; Epithelium; Event; Female; Fibroblasts; Genes; Genetic Transcription; Histones; Hormonal; Human; In Vitro; Induced Labor; Inflammatory; Labor Onset; Laboratory Finding; Length; Luteolysis; Lysine; Mechanics; Mediator; Molecular; Mus; Nature; Ovary; Pathway interactions; Perinatal mortality demographics; Phenotype; Play; Pregnancy; Pregnancy Complications; Premature Birth; Process; Production; Progesterone; Prostaglandin Antagonists; Prostaglandin Production; Prostaglandin-Endoperoxide Synthase; Prostaglandins; Protein Isoforms; Publishing; Regulation; Research; Rodent; Role; Signal Transduction; Therapeutic; Time; Tissues; Uterus; cell type; cyclooxygenase 1; demethylation; design; diagnostic value; experience; experimental study; inhibitor; insight; interstitial; member; myometrium; novel; perinatal morbidity; pharmacologic; prevent; programs; single-cell RNA sequencing; stem; transcriptome sequencing; uterine contractility

Project Summary (Abstract) Preterm birth (PTB) is the global leading cause of death for children under the age of five. In large part, this high burden results from our limited understanding of the mechanisms controlling normal parturition. In mice, one parturition pathway involves increased uterine epithelial cell expression of the prostaglandin synthase COX-1. COX-1 then allows the uterus to produce prostaglandin PGF2α, which turns off progesterone production by the ovary. How this important enzyme is regulated, however, remains unknown. This proposal is based upon my unpublished data that epigenetic pathways play a central role in the induction of COX-1 expression by uterine epithelial cells and hence initiation of the labor cascade in mice. Specifically, I have found that mice engineered to lack uterine expression of KDM6B, a histone H3K27me3 demethylase, show delayed parturition associated with reduced COX-1 expression by luminal epithelial cells. Motivated by this data, my two Specific Aims will seek to identify (1) the cellular and molecular circuitry and downstream events through which KDM6B induces parturition; and (2) the upstream regulators of KDM6B activity. Results from these studies will provide clear cellular and molecular definition to a key regulatory circuit that initiates parturition in mice, potentially including the identification of epigenetic components of the long-mysterious gestation length “timer.” As such, they might open new avenues for dissecting the mechanisms of human parturition and for determining how such mechanisms are dysregulated in human pregnancy complications like preterm birth.

项目摘要（摘要） 早产（PTB）是全球五岁以下儿童死亡的主要原因。在很大程度上，这 高负担是由于我们对控制正常分娩的机制了解有限。在小鼠中， 一种分娩途径涉及前列腺素合酶的子宫上皮细胞表达增加 考克斯-1。然后，考克斯-1允许子宫产生前列腺素PGF 2 α，从而关闭孕酮 由卵巢产生。然而，这种重要的酶是如何调节的仍然是未知的。 这个建议是基于我未发表的数据，即表观遗传途径在诱导中起着核心作用。 小鼠子宫上皮细胞表达考克斯-1，从而启动分娩级联反应。我特别 已经发现，通过基因工程使小鼠的子宫中缺乏KDM 6 B的表达，KDM 6 B是一种组蛋白H3 K27 me 3去甲基化酶， 显示延迟分娩与腔上皮细胞表达的降低的考克斯-1相关。出于 这些数据，我的两个具体目标将寻求确定（1）细胞和分子电路和下游 KDM 6 B诱导分娩的事件;和（2）KDM 6 B活性的上游调节物。结果 从这些研究中将提供清晰的细胞和分子定义的关键调控电路，启动 小鼠分娩，可能包括鉴定长期神秘的 妊娠时间“计时器”。因此，它们可能为解剖人类的机制开辟新的途径。 以及确定这些机制在人类妊娠并发症中如何失调， 早产。