(INTRODUCTION) MECHANISMS OF ACCLIMATIZATION: FETUS AND ADULT

（简介）适应机制：胎儿和成人

基本信息

批准号：
8516067
负责人：
LAWRENCE D LONGO
金额：
$ 133.88万
依托单位：
LOMA LINDA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-01-01 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8516067
关键词：
Acclimatization Acute Adrenal Glands Adrenergic Agents Adrenergic Receptor Adult Altitude Altitude Sickness Arteries Biochemical Blood Circulation Blood flow Cardiovascular Diseases Cerebral Edema Cerebral hemisphere hemorrhage Chronic Clinical Coupling Development Disease Endothelium Extracellular Signal Regulated Kinases Fetus Heart Diseases Hydrocortisone Hypoxia Life Light Lung diseases Mediating Microfilaments Molecular Mothers Nerve Newborn Infant Nitric Oxide Physiological Placental Insufficiency Pre-Eclampsia Pregnancy Protein Isoforms Protein Kinase C Pulmonary Edema Pulmonary Hypertension Regulation Research Role Sheep Signal Transduction Smoke Smooth Muscle Structure Testing Thick Vascular Endothelial Growth Factors Woman adrenergic base cerebral artery cerebrovascular developmental plasticity disorder risk fetal maternal stress multidisciplinary prenatal programs public health relevance response steroid hormone

项目摘要

DESCRIPTION (provided by applicant): The overall theme of this application is to explore fundamental mechanisms whereby the fetus and adult acclimatize to high altitude, long-term hypoxia (LTH). In addition, we will examine these mechanisms in association with development from fetus to adult. This application is a broadly based, multidisciplinary integrated program using physiologic, pharmacologic, cellular, biochemical, and molecular approaches. Based on >21 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, LTH causes coordination of systemic, cellular, and subcellular responses in the mother and fetus, significantly impacting developmental plasticity and subsequent risk for disease. In cerebral arteries, we will test hypotheses regarding Oi-adrenergic-mediated signal transduction mechanisms for both Ca^*-dependent and Ca^^-independent regulation of thin and thick myofilament, e.g., roles of alphal adrenergic receptor subtypes, protein kinase C isoforms, extracellular signal regulated kinases, and coupling to downstream effectors. We will test the hypothesis that hypoxic acclimatization effects on arterial structure and function are mediated by vascular endothelial growth factor and its effects on the smooth muscle, endothelium, and perivascular nerves of fetal cerebral arteries. In addition, we will explore the role of perivascular nerves in cerebrovascular reactivity. In uterine arteries, we will examine mechanisms of steroid hormones in maladaptation of uterine circulation caused by LTH in pregnancy. Finally, we will explore how LTH alters the role of nitric oxide in the regulation of fetal adrenal Cortisol synthesis. Scientifically the studies will augment our understanding of mechanisms whereby fetus and adult acclimatize to LTH. 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 prenatal "programming" of adult disease. 3) Finally, the studies are relevant to understanding mechanisms of diseases, including: Acute Mountain Sickness, Preeclampsia, and High Altitude Cerebral and Pulmonary Edema. PUBLIC HEALTH RELEVANCE: Scientifically, the studies will augment our understanding of basic mechanisms whereby fetus and adult acclimatize to chronic hypoxia. From a clinical standpoint, these studies relate to important problems: fetus and newborn responses to hypoxia as occurs in women at high altitude, as well as those who are anemic, or who have heart or lung disease, altered cerebrovascular blood flow with intracerebral hemorrhage and pulmonary hypertension, and mechanisms of maternal stress and prenatal "programming" understanding mechanisms of acute mountain sickness, preeclampsia, and high altitude cerebral and pulmonary edema.

描述（由申请人提供）：本申请的总体主题是探索基本机制，从而使胎儿和成人适应高海拔，长期缺氧（LTH）。此外，我们将研究这些机制，这些机制与从胎儿到成人的发展有关。该应用是一种基于生理，药理，细胞，生化和分子方法的广泛的，多学科的综合程序。根据我们小组的21年研究，将在适应高海拔的绵羊（3801 m/12,470 ft）中进行研究。我们将检验许多假设。总体假设是，高海拔，LTH会导致母亲和胎儿的全身，细胞和亚细胞反应的协调，从而显着影响发育性可塑性以及随后的疾病风险。 In cerebral arteries, we will test hypotheses regarding Oi-adrenergic-mediated signal transduction mechanisms for both Ca^*-dependent and Ca^^-independent regulation of thin and thick myofilament, e.g., roles of alphal adrenergic receptor subtypes, protein kinase C isoforms, extracellular signal regulated kinases, and coupling to downstream effectors.我们将检验以下假设：低氧适应对动脉结构和功能的影响是由血管内皮生长因子及其对平滑肌，内皮和胎儿大脑动脉血管周围神经的影响介导的。此外，我们将探索血管神经在脑血管反应性中的作用。在子宫动脉中，我们将检查类固醇激素的机制子宫循环的疾病在怀孕中由LTH引起的疾病。最后，我们将探讨LTH如何改变一氧化氮在调节胎儿肾上腺皮质醇合成中的作用。从科学上讲，这些研究将增强我们对胎儿和成人适应LTH的机制的理解。此外，他们将阐明成熟发展的许多方面。从临床角度来看，这些研究至少涉及三个重要问题。 1）对于胎儿和新生儿而言，它们与居住在高海拔地区的女性以及吸烟或贫血的女性，患有心脏或肺部疾病或“胎盘不足”的妇女有关。对于新生儿，它们与脑血管血流的改变有关，脑出血和肺动脉高压。 2）研究还将有助于理解成人疾病的母体心血管疾病和产前“编程”的机制。 3）最后，研究与理解疾病机制有关，包括：急性山疾病，先兆子痫和高海拔大脑和肺水肿。公共卫生相关性：从科学上讲，这些研究将增强我们对胎儿和成人对慢性缺氧的基本机制的理解。从临床角度来看，这些研究与重要问题有关：高空高空的女性以及贫血的女性以及患有心脏或肺部疾病的胎儿和新生儿对缺氧的反应，改变了脑血管血液流动，并随着脑内出血，脑部出血，肺部的压力和肺部压力和机制的疾病和机制，理解了孕产妇的疾病和机制。高海拔大脑和肺水肿。