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

• 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
• 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

 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（由适用提供）：怀孕期间子宫血流的惊人增加对于胎儿的最佳生长和母亲的心血管福祉至关重要。妊娠期间子宫循环的适应不良与包括先兆子痫和胎儿发育异常在内的临床并发症的高发病率有关。大传导CA2+激活的K+（BKCA）通道在调节子宫流动妊娠中起着至关重要的作用。最近对绵羊的研究表明，妊娠和类固醇激素导致BKCAβ1亚基的显着增加，导致β1：α亚基化学计量法和子宫动脉中BKCA通道活性的增强。然而，分子机制仍然未知。我们的初步研究表明，妊娠和类固醇激素在β1基因启动子处导致DNA甲基化降低。 DNA甲基化是表观遗传表达模式中的主要机制。最近的研究表明，活性DNA脱甲基化中十个时期易位1-3（TET1-3）蛋白的鲁棒机制。初步研究表明，妊娠和类固醇激素增加了子宫动脉中TET1-2的表达。这些发现导致了对高度新颖机制的研究，该研究检验了类固醇激素介导的DNA甲基化和脱甲基化的动态变化的假设，在控制子宫血管对妊娠的BKCA通道的表达和功能中起着关键作用。两个具体的目的将确定：1）类固醇激素介导的启动子脱甲基化和BKCAβ1基因上调在妊娠子宫动脉中增加的BKCA通道功能中起因果作用，而2）类固醇激素介导的TET1-3在TET1-3中扮演TET1-3在Active DNA降解中的作用在孕妇中的促成和β1β1β1β1β1β1β1β1β1β1β1β1β11-11-3。拟议的研究提出了研究的主要突破和范式转移的重点，目的是阐明在子宫血管中，特别是在调节基因表达模式中，特别是在血管平滑肌肉功能中，在调节基因表达模式中，本元介导的DNA脱甲基化的高度表观遗传机制。拟议的研究的结果将显着提高我们在子宫牙科适应妊娠的分子机制方面的知识，并提高我们对子宫循环和妊娠并发症不适的病理生理机制的理解。由于BKCA渠道在控制血管张力和压力几乎所有血管床中的功能至关重要，并且对BKCA渠道表达和血管平滑肌的活性的表观遗传调节的知识极为有限，因此拟议的研究确实将对调节BKCA信道活性和血管学的分子机制的全面理解具有很大的影响。