Understanding the role of KDM6B in parturition onset

了解 KDM6B 在分娩开始中的作用

• 批准号: 10464768
• 负责人: Tara Mcintyre
• 金额: $ 3.88万
• 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/10464768
• 关键词: Age; Biology; Birth; Cause of Death; Child; Coculture Techniques; Complex; Data; Developed Countries; Endometrium; Engineering; Enzymes; Epigenetic Process; Epithelial; Epithelial Cells; Event; Female; Fibroblasts; Genes; Genetic Transcription; Histones; Hormonal; Human; In Vitro; Induced Labor; Inflammatory; Labor Onset; Length; Luteolysis; Lysine; Mechanics; Mediator of activation protein; Molecular; Mus; Nature; Ovary; Pathway interactions; Perinatal mortality demographics; Pharmacology; 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; base; cell type; cyclooxygenase 1; demethylation; design; diagnostic value; experience; experimental study; inhibitor; insight; interstitial; member; myometrium; novel; perinatal morbidity; 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 This proposal is based upon my unpublished data that epigenetic pathways play a central role in the induction of COX-1 expression by uterine epithelial cells and hence initiation of the labor cascade in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）是五岁以下儿童的全球主要死亡原因。在很大程度上，这个 高燃烧是由于我们对控制正常分娩的机制的有限理解。在老鼠中， 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 COX-1。然后，COX-1允许子宫产生前列腺素PGF2α，该PGF2α关闭孕酮 卵巢生产。但是，如何调节这种重要的酶仍然未知。 该提议基于我未发表的数据，即表观遗传途径在归纳中起着核心作用 子宫上皮细胞的COX-1表达，因此小鼠劳动级联的倡议。具体来说，我 发现小鼠设计为缺乏子宫表达KDM6B，一种组蛋白H3K27ME3脱甲基酶， 显示与腔上皮细胞降低的COX-1表达相关的延迟分娩。动机 这些数据，我的两个具体目标将寻求识别（1）细胞和分子电路以及下游 KDM6B诱导分娩的事件； （2）KDM6B活动的上游调节剂。结果 从这些研究中，将为启动的关键调节电路提供明显的细胞和分子定义 小鼠的分娩，有可能包括鉴定长期遗传成分 妊娠长度“计时器”。因此，他们可能会为剖析人类机制开辟新的途径 分娩并确定这种机制如何在人类妊娠并发症中失调 早产。