Gestational Hypoxia and Developmental Plasticity

妊娠缺氧与发育可塑性

• 批准号: 9241396
• 负责人: Lubo Zhang
• 金额: $ 125.53万
• 依托单位: LOMA LINDA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9241396
• 关键词: Acclimatization; Acute; Adipose tissue; Adrenergic Receptor; Adult; Adverse effects; Altitude; Altitude Sickness; Animals; Applications Grants; Arteries; Attenuated; Biochemical; Biology; Blood Vessels; Brown Fat; Calcium-Activated Potassium Channel; Cardiac; Cardiovascular Diseases; Cerebral Edema; Cerebral hemisphere hemorrhage; Cerebrovascular Circulation; Characteristics; Chronic; Clinical; Clinical Management; DNA Methylation; Development; Disease; Down-Regulation; Endocrine; Enzymes; Epigenetic Process; Fetal Development; Fetus; Funding; Gene Expression Profile; Genes; Goals; Health; Heart Diseases; Hypoxemia; Hypoxia; Ion Channel; Light; Lung; Lung diseases; Maternal Health; Mediating; Membrane; MicroRNAs; Modification; Molecular; Mothers; Myosin Light Chain Kinase; Newborn Infant; Organism; Oxygen; Perinatal; Perinatal mortality demographics; Pharmacology; Physiological; Placental Insufficiency; Play; Positioning Attribute; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Program Research Project Grants; Property; Protein Kinase; Pulmonary Edema; Pulmonary Hypertension; Regulation; Research; Research Personnel; Risk; Role; Sea; Series; Sheep; Signaling Protein; Smoke; Stress; System; Testing; Tissues; Translations; Universities; Woman; attenuation; base; cell type; cerebral artery; cerebrovascular; clinically relevant; demethylation; developmental plasticity; disorder risk; experimental study; fetal; gestational hypoxia; histone modification; improved; inhibitor/antagonist; innovation; insight; multidisciplinary; myometrium; neonatal outcome; novel; perinatal morbidity; pregnant; programs; public health relevance; receptor; relating to nervous system; response; steroid hormone

 DESCRIPTION (provided by applicant): The overall theme of this proposal is to explore fundamental mechanisms whereby the mother and her fetus acclimatize to high altitude, long-term hypoxia. In addition, we will examine the mechanisms in association with development from fetus to adult. Hypoxia is one of the most common and severe stresses to an organism's homeostatic mechanisms and hypoxia during gestation have profound adverse effects on maternal health and developmental plasticity. Much remains unknown of the molecular mechanisms in response to long-term hypoxia in both the fetus and adult. This proposal is a broadly based, multidisciplinary, integrated program using physiological, pharmacological, cellular, biochemical, and molecular approaches. Based on >25 years of research by our group, studies will be conducted in sheep acclimatized to high altitude (3801 m/12,470 ft.). We shall test a number of hypotheses. The overall hypothesis is that high altitude, long-term hypoxia during gestation results in epigenetic-mediated molecular modifications of systemic and cellular and sub-cellular responses in the mother and her fetus, significantly impacting developmental plasticity and the subsequent risk for disease. In uterine arteries, we will test the hypothesis tht steroid hormone-induced dynamic, epigenetic-mediated changes of DNA methylation and demethylation play a key role in regulating expression and function of large- conductance Ca2+-activated K+ channels in uterine vascular adaptation to pregnancy and chronic hypoxia. In cerebral arteries, we will test the hypothesis that epigenetic-related mechanisms such as DNA methylation, histone modifications and microRNA play a key role in regulating expression and function of α1-adrenoceptor subtypes in cerebral arteries in response to development and chronic hypoxia. We will determine the role of α1- adrenoceptor subtypes in sympathetic system-mediated regulation of cerebral blood flow, as well as to examine the effects of inhibitors of DNA methylation, histone modification and microRNA on α1-adrenoceptor subtype- mediated cerebral blood flow regulation in normoxic and high altitude hypoxic fetus and adult sheep. In addition, we will test the hypothesis that chronic hypoxia attenuates vascular contractility in general, and cerebrovascular contractility in particular, through down-regulation of myosin light chain kinase (MLCK) activity via a microRNA- mediated decrease in translation of MLCK message, an increase in proteosomal degradation of MLCK protein, and attenuation of MLCK specific activity. Finally, we will test the hypothesis that gestational hypoxia alters molecular ad epigenetic mechanisms in regulating signaling protein gene expression patterns, resulting in reprogramming of brown adipose tissue characteristics/function in perirenal adipose tissue of the developing fetus and lamb. Scientifically the proposed studies will augment our understanding of molecular and epigenetic mechanisms in regulating the expression and function of several important genes including ion channels, membrane receptors, key enzymes and signaling proteins in maternal and fetal vasculatures and adipose tissue in response to long-term hypoxia. In addition, they will shed light on a number of aspects of maturational development. From a clinical standpoint, these studies relate to at least three important problems. 1) For the fetus and newborn they relate to responses to prolonged hypoxia as occurs in women who live at high altitude, as well as those who smoke or are anemic, who have heart or lung disease, or with "placental insufficiency." For newborn they relate to altered cerebrovascular blood flow with intracerebral hemorrhage and pulmonary hypertension. 2) The studies also will contribute to understanding mechanisms of maternal cardiovascular disorders and developmental "programming" of health and disease. 3) Finally, in the adult the studies are relevant to understanding mechanisms of diseases, including acute mountain sickness, preeclampsia, and high altitude cerebral and pulmonary edema.

 描述（由申请人提供）：本提案的总体主题是探索母亲及其胎儿适应高海拔、长期缺氧的基本机制。此外，我们将研究与从胎儿到成人的发展相关的机制。缺氧是机体内环境稳定机制最常见和最严重的应激之一，妊娠期缺氧对母体健康和发育可塑性有深远的不利影响。胎儿和成人长期缺氧的分子机制仍不清楚。该提案是一个基础广泛的，多学科的，综合计划，采用生理学，药理学，细胞，生物化学和分子方法。基于我们小组超过25年的研究，将在适应高海拔（3801米/12，470英尺）的绵羊中进行研究。我们将检验一些假设。总体假设是，妊娠期间的高海拔、长期缺氧导致母亲及其胎儿的全身、细胞和亚细胞反应的表观遗传介导的分子修饰，显著影响发育可塑性和随后的疾病风险。在子宫动脉中，我们将检验类固醇激素诱导的动态的、表观遗传介导的DNA甲基化和去甲基化的变化在调节大电导Ca 2+激活的K+通道的表达和功能中起关键作用的假设，所述大电导Ca 2+激活的K+通道在子宫血管对妊娠和慢性缺氧的适应中。在脑动脉中，我们将检验这样的假设，即表观遗传相关机制如DNA甲基化、组蛋白修饰和microRNA在调节脑动脉中α1-肾上腺素受体亚型的表达和功能中起关键作用，以响应发育和慢性缺氧。我们将确定α1-肾上腺素能受体亚型在交感系统介导的脑血流调节中的作用，以及在常氧和高原缺氧胎儿和成年绵羊中检测DNA甲基化、组蛋白修饰和microRNA抑制剂对α1-肾上腺素能受体亚型介导的脑血流调节的影响。此外，我们将检验慢性缺氧通过microRNA介导的肌球蛋白轻链激酶（MLCK）信息翻译减少、MLCK蛋白质的蛋白体降解增加和MLCK比活性减弱而下调MLCK活性，从而总体上减弱血管收缩力，特别是脑血管收缩力的假设。最后，我们将测试这一假设，即妊娠缺氧改变调节信号蛋白基因表达模式的分子和表观遗传机制，导致发育中胎儿和羔羊肾周脂肪组织中棕色脂肪组织特征/功能的重编程。科学上，拟议的研究将增加我们对调节几个重要基因的表达和功能的分子和表观遗传机制的理解，这些基因包括离子通道，膜受体，关键酶和信号蛋白，在母体和胎儿血管和脂肪组织中响应长期缺氧。此外，他们将阐明一些方面的成熟发展。从临床角度来看，这些研究至少涉及三个重要问题。1)对于胎儿和新生儿，它们与长时间缺氧的反应有关，如生活在高海拔地区的妇女，以及吸烟或贫血的妇女，患有心脏或肺部疾病或“胎盘功能不全”的妇女。“对于新生儿，它们与脑血管血流改变、脑出血和肺动脉高压有关。2)这些研究还将有助于了解产妇心血管疾病的机制以及健康和疾病的发展“规划”。3)最后，在成人中，这些研究与理解疾病的机制有关，包括急性高原病，先兆子痫，高海拔脑水肿和肺水肿。