DNA Demethylation and BKca Channel Expression and Function in Uterine Arteries

子宫动脉中 DNA 去甲基化和 BKca 通道表达和功能

基本信息

批准号：
8858032
负责人：
Lubo Zhang
金额：
$ 23.7万
依托单位：
LOMA LINDA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-03-01 至 2017-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8858032
关键词：
Adult Arteries Blood Vessels Blood flow Cardiovascular system Clinical Clinical Management DNA DNA Methylation Down-Regulation Employee Strikes Epigenetic Process Fetal Development Fetal Growth Retardation Fetus Functional disorder Gene Expression Profile Genes Growth Hormones Hydroxylation Incidence Investigation Knowledge Lead Maternal Health Mediating Methylation Modification Molecular Morbidity - disease rate Mothers Muscle function Neonatal Outcome Perinatal Personal Satisfaction Physiology Play Pre-Eclampsia Pregnancy Pregnancy Complications Promoter Regions Proteins Repression Research Role Series Sheep Testing Time Tissues Up-Regulation Uteroplacental Circulation Vascular Smooth Muscle demethylation epigenetic regulation fetal gene repression improved inhibitor/antagonist innovation insight novel pregnant pressure promoter public health relevance research study steroid hormone stoichiometry vascular bed

项目摘要

DESCRIPTION (provided by applicant): The striking increase of uterine blood flow during pregnancy is essential both for optimal growth of the fetus and cardiovascular well-being of the mother. Maladaptation of the uteroplacental circulation during gestation is associated with high incidence of clinical complications including preeclampsia and fetal development abnormality. Large-conductance Ca2+-activated K+ (BKCa) channels play a critical role in regulating uterine blood flow in pregnancy. Recent studies in sheep demonstrated that pregnancy and steroid hormones caused a significant increase in BKCa β1 subunit resulting in increased β1:α subunit stoichiometry and heightened BKCa channel activity in uterine arteries. Yet the molecular mechanisms remain unknown. Our preliminary studies showed that pregnancy and steroid hormones caused a decrease in DNA methylation at the β1 gene promoter. DNA methylation is a chief mechanism in epigenetic repression of gene expression patterns. Recent studies suggest a robust mechanism of ten-eleven translocation 1-3 (TET1-3) proteins in active DNA demethylation. Preliminary studies suggested that pregnancy and steroid hormones increased TET1-2 expression in uterine arteries. These findings lead to the proposed studies of a highly novel mechanism testing the hypothesis that steroid hormone-mediated dynamic changes of DNA methylation and demethylation play a key role in regulating expression and function of BKCa channels in uterine vascular adaptation to pregnancy. Two specific aims will determine whether: 1) steroid hormone-mediated promoter demethylation and BKCa β1 gene up- regulation play a causal role in increased BKCa channel function in uterine arteries in pregnancy, and 2) steroid hormone-mediated up-regulation of TET1-3 plays a causal role in active DNA demethylation and the β1 gene up-regulation in pregnancy. The proposed study presents a major breakthrough and paradigm-shifting focus of research aiming at unraveling highly novel epigenetic mechanisms of hormone-mediated DNA demethylation in regulating gene expression patterns in uterine vasculature in particular, and in vascular smooth muscle function in general. The outcome of the proposed study will significantly advance our knowledge in molecular mechanisms of uteroplacental adaptation to pregnancy and improve our understanding of pathophysiological mechanisms underlying maladaptation of uteroplacental circulation and pregnancy complications. Because of the vital importance of BKCa channel function in regulating vascular tone and pressure in virtually all vascular beds, and the extremely limited knowledge in epigenetic regulation of BKCa channel expression and activity in vascular smooth muscle, the proposed study will indeed have a much broad impact in comprehensive understanding of molecular mechanisms in regulating BKCa channel activity and vascular function in physiology and pathophysiology.

描述（由申请人提供）：妊娠期间子宫血流量的显着增加对于胎儿的最佳生长和母亲的心血管健康至关重要。妊娠期间子宫胎盘循环的适应不良与临床并发症的高发生率相关，其中包括。先兆子痫和胎儿发育异常。大电导 Ca2+ 激活的 K+ (BKCa) 通道在妊娠期子宫血流调节中发挥着关键作用。妊娠和类固醇激素导致 BKCa β1 亚基显着增加，从而导致子宫动脉中 β1:α 亚基化学计量增加和吞咽 BKCa 通道活性，但我们的初步研究表明，妊娠和类固醇激素导致 BKCa 减少。 β1 基因启动子处的 DNA 甲基化是基因表达模式表观遗传抑制的主要机制。最近的研究表明，10-11 易位 1-3 是一种强有力的机制。 (TET1-3) 蛋白的 DNA 高度去甲基化初步研究表明，妊娠和类固醇激素增加了子宫动脉中的 TET1-2 表达。这些发现导致了对类固醇激素介导的动态变化假设的新机制的研究。 DNA 甲基化和去甲基化在调节 BKCa 通道在子宫血管适应妊娠中的表达和功能中发挥关键作用，两个具体目标将决定是否：1）类固醇激素介导的启动子去甲基化和 BKCa。 β1 基因上调在妊娠期子宫动脉 BKCa 通道功能增强中起因果作用，2）类固醇激素介导的 TET1-3 上调在主动 DNA 去甲基化和妊娠期 β1 基因上调中起因果作用。这项研究提出了一项重大突破和范式转变的研究重点，旨在揭示激素介导的 DNA 去甲基化在调节子宫脉管系统（特别是血管）基因表达模式方面的高度新颖的表观遗传机制。由于 BKCa 通道功能的重要性，本研究的结果将显着提高我们对子宫胎盘适应妊娠的分子机制的认识，并提高我们对子宫胎盘循环适应不良和妊娠并发症的病理生理机制的理解。在调节几乎所有血管床的血管张力和压力方面，以及对血管平滑肌中 BKCa 通道表达和活性的表观遗传调节的了解极其有限，拟议的研究确实会对全面理解产生广泛的影响生理学和病理生理学中调节 BKCa 通道活性和血管功能的分子机制。