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

项目摘要。这个项目的总主题是更深层次地了解 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)习服。这个项目是 使用生理、细胞、生物化学和分子进行广泛和垂直集成 四名调查员接受了多学科和方法论方面的培训。基于 25年来对脑血管调节的深入研究 反应性，我们将检验对长期低氧的适应是中介的假设， 重要的和部分通过表观遗传介导的α1-肾上腺素能受体(α1-AR)亚型 (α1A、α1B、-α1D)，以及它们在基因转录中各自独特的作用。我们的具体目标 包括测试几个关于长期缺氧和 发育成熟：DNA甲基化在转录中的作用是什么 阿尔法1-AR亚型？组蛋白修饰(乙酰化、甲基化和 其他)在α1-AR亚型介导的转录中？低氧调节的作用是什么？ 在这方面的microRNAs？交感神经支配和α1-AR亚型在脑出血中的作用 脑血流量调节？DNA甲基化，组蛋白乙酰化， 组蛋白甲基化，MicroRNA介导的α1-AR亚型在脑血流调节中的作用 LTH的后果？从科学上讲，这些研究将增加我们对基础知识的理解 胎儿和成人脑血管适应LTH的机制。他们也会 说明从胎儿到成人的发育调控的各个方面。在临床上，这些研究与 至少有三个关键问题。1)对胎儿和新生儿的反应 长期低氧，发生在生活在高海拔地区的女性，以及吸烟或 贫血，患有心脏病或肺病；对于新生儿脑血管血流改变 并伴有脑出血和肺动脉高压。2)他们还将为 理解表观遗传介导的心血管疾病和产前发病机制 对成人疾病的“编程”。这包括交感神经在这方面的作用。 3)此外，它们还与理解表观遗传介导的疾病机制有关。 如：急性高原反应、先兆子痫、高原脑肺 浮肿。

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.