Understanding the role of KDM6B in parturition onset

项目摘要(摘要) 早产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造成的。在老鼠身上， 一种分娩途径涉及子宫上皮细胞前列腺素合成酶的表达增加 COX-1。然后，环氧合酶-1允许子宫产生前列腺素PGF2α，从而关闭孕酮 由卵巢产生的。然而，这种重要的酶是如何调节的，目前尚不清楚。 这一建议是基于我未发表的数据，即表观遗传途径在诱导过程中发挥核心作用。 环氧合酶-1在子宫上皮细胞中的表达，从而启动了小鼠的分娩过程。具体来说，我 他们发现，经过基因改造的小鼠缺乏KDM6B的子宫表达，KDM6B是一种组蛋白H3K27me3去甲基酶， 显示延迟分娩与腔上皮细胞环氧合酶-1表达减少有关。动机是 这些数据，我的两个具体目标将寻求确定(1)细胞和分子的电路和下游 KDM6B诱导分娩的事件；(2)KDM6B活性的上游调节因子。结果 这些研究将为启动关键调控回路提供明确的细胞和分子定义 小鼠的分娩，可能包括鉴定表观遗传成分的长期神秘 妊娠长度计时器。因此，它们可能会为剖析人类的机制开辟新的途径 并确定这些机制在人类妊娠并发症中是如何失调的，如 早产。

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 This proposal is based upon my unpublished data that epigenetic pathways play a central role in the induction of COX-1 expression by uterine epithelial cells and hence initiation of the labor cascade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