Mechanisms of acclimatization responses of fetal and adult cerebral artery alpha1 adrenergic receptor subtypes to long-term hypoxia

胎儿和成人脑动脉α1肾上腺素能受体亚型对长期缺氧的适应反应机制

• 批准号: 9072344
• 负责人: Ravi Goyal
• 金额: $ 18.91万
• 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/9072344
• 关键词: AR gene; Acclimatization; Acetylation; Acute; Adrenergic Agents; Adrenergic Receptor; Adult; Altitude; Altitude Sickness; Animals; Arteries; Azacitidine; Biochemical; Blood flow; Books; Brain; Cardiovascular Diseases; Carotid Arteries; Cerebral Edema; Cerebral hemisphere hemorrhage; Cerebrovascular Circulation; Cerebrovascular system; Cerebrum; Chronic; Chronic stress; DNA; DNA Methylation; Development; Discipline; Disease; Epigenetic Process; Fetal Growth Retardation; Fetus; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Heart Diseases; Histone Acetylation; Human; Hypoxia; Immunofluorescence Immunologic; Individual; Investigation; Life; Long-Term Effects; Lung diseases; Measures; Mediating; Messenger RNA; Methodology; Methylation; MicroRNAs; Modification; Molecular; Neonatal; Nerve; Newborn Infant; Norepinephrine; Phenotype; Phenylephrine; Physiological; Plasma; Play; Pre-Eclampsia; Publishing; Pulmonary Edema; Pulmonary Hypertension; Regulation; Resistance; Role; Sheep; Signal Transduction; Smoke; Stress; Testing; Time; Tissues; Transferase; Translational Regulation; Translations; Validation; Vascular Smooth Muscle; Western Blotting; Woman; Work; age group; base; cerebral artery; cerebrovascular; developmental plasticity; epigenetic regulation; fetal; histone acetyltransferase; histone methylation; histone methyltransferase; histone modification; in vivo; inhibitor/antagonist; insight; investigator training; middle cerebral artery; nerve supply; pregnant; prenatal; prenatal stress; programs; promoter; receptor; research study; response; vascular smooth muscle cell proliferation

Project Summary. The overall theme of this project is to understand at a deeper level the epigenetic-mediated signal transduction mechanisms by which the cerebrovasculature in the fetus and adult become acclimatized to high altitude, long-term hypoxia (LTH). This project is broadly based and vertically integrated using physiological, cellular, biochemical, and molecular approaches by four investigators trained in multiple disciplines and methodologies. Based on over two and one-half decades of intense investigation of the regulation of cerebrovascular reactivity, we shall test the hypothesis that acclimatization to long-term hypoxia is mediated, importantly and in part by epigenetic-mediated alpha1-adrenergic receptor (α1-AR) subtypes (α1A, α1B, - α1D), and their individual and unique roles in gene transcription. Our Specific Aims involve testing several associated hypotheses regarding both long-term hypoxia and developmental maturation including that of: What is the role of DNA methylation on transcription of alpha1-AR subtypes? What is the role of histone modifications (acetylation, methylation, and others) in α1-AR subtype-mediated transcription? What is the role of hypoxic-mediated microRNAs in this regard? What is the role of sympathetic innervation and α1-AR subtype in cerebral blood flow (CBF) regulation? What is the role of DNA methylation, histone acetylation, histone methylation, microRNA-mediated regulation of α1-AR subtype in CBF regulation as a consequence of LTH.?Scientifically the studies will augment our understanding of basic mechanisms whereby fetal and adult cerebral vessels acclimatize to LTH. They also will illustrate aspects of developmental regulation from fetus to adult. Clinically the studies relate to at least three critical 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; for the newborn altered cerebrovascular blood flow with intracerebral hemorrhage and pulmonary hypertension. 2) They also will contribute to understanding the epigenetic-mediated mechanisms of cardiovascular disorders and prenatal “programming” of adult disease. This includes the role of sympathetic innervation in this regard. 3) In addition, they are relevant to understanding epigenetic-mediated mechanisms of diseases such as: Acute Mountain Sickness, Preeclampsia, and High Altitude Cerebral and Pulmonary Edema.

项目摘要。本项目的总体主题是在更深层次上理解 表观遗传介导的信号转导机制， 胎儿和成人对高海拔长期缺氧（LTH）适应。这个项目是 利用生理学、细胞学、生物化学和分子生物学， 四名接受过多种学科和方法培训的调查员采用了不同的方法。基于 经过25年对脑血管调节的深入研究， 反应性，我们将测试的假设，适应长期缺氧介导， 重要的是部分通过表观遗传介导的α 1-肾上腺素能受体（α1-AR）亚型 （α1A，α1B，- α1D），以及它们在基因转录中的个体和独特作用。我们的具体目标 涉及测试几个相关的假设，关于长期缺氧和 发育成熟包括：DNA甲基化对转录的作用是什么 α 1-AR亚型组蛋白修饰（乙酰化，甲基化， 其他）在α1-AR亚型介导的转录？缺氧介导的作用是什么 microRNA在这方面？交感神经支配和α1-AR亚型在 脑血流量（CBF）调节？DNA甲基化，组蛋白乙酰化， 组蛋白甲基化、microRNA介导的α1-AR亚型在CBF调节中的作用 LTH的后果。科学地说，这些研究将增加我们对基本的 胎儿和成人脑血管适应LTH的机制。他们还将 说明从胎儿到成人发育调节方面。临床研究涉及 至少有三个关键问题。1)对于胎儿和新生儿，它们与以下反应有关： 长期缺氧发生在生活在高海拔地区的妇女，以及那些吸烟或 贫血，患有心脏或肺部疾病;对于新生儿脑血管血流改变 脑出血和肺动脉高压2)他们也将有助于 了解心血管疾病的表观遗传介导机制， 成人疾病的“编程”这包括交感神经支配在这方面的作用。 3)此外，它们与理解疾病的表观遗传介导机制有关 如：急性高原病，先兆子痫，高海拔脑和肺 水肿