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 This proposal is based upon my unpublished data that epigenetic pathways play a central role in the induction of COX-1 expression by uterine epithelial cells and hence initiation of the labor cascade in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）