(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胎儿和成人适应高海拔、长期缺氧（LTH）的基本机制。此外，我们将研究这些机制与从胎儿到成人发育的关系。该应用是一个基础广泛、多学科的综合项目，使用生理学、药理学、细胞、生化和分子方法。基于我们小组超过 21 年的研究，研究将在适应高海拔（3801 m/12,470 英尺）的绵羊中进行。我们将检验一些假设。总体假设是，高海拔、LTH 会导致母亲和胎儿的系统、细胞和亚细胞反应协调，显着影响发育可塑性和随后的疾病风险。在脑动脉中，我们将测试有关 Oi 肾上腺素介导的信号转导机制的假设，以实现细肌丝和粗肌丝的 Ca^* 依赖性和 Ca^^ 独立调节，例如 α1 肾上腺素受体亚型、蛋白激酶 C 亚型的作用、细胞外信号调节激酶，以及与下游效应器的偶联。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介导的，及其对胎儿脑动脉的平滑肌、内皮和血管周围神经的影响。此外，我们还将探讨血管周围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妊娠期LTH引起的子宫循环适应不良。最后，我们将探讨 LTH 如何改变一氧化氮在胎儿肾上腺皮质醇合成调节中的作用。从科学角度来说，这些研究将增强我们对胎儿和成人适应 LTH 机制的理解。此外，它们还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，它们与长期缺氧的反应有关，如生活在高海拔地区的女性、吸烟者或贫血者、患有心脏病或肺病或“胎盘功能不全”的女性。对于新生儿来说，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孕产妇心血管疾病的机制和成人疾病的产前“编程”。 3) 最后，这些研究与了解疾病的机制有关，包括：急性高山病、先兆子痫、高原脑水肿和肺水肿。公共卫生相关性：从科学角度来说，这些研究将增强我们对胎儿和成人适应慢性缺氧的基本机制的理解。从临床角度来看，这些研究涉及重要问题：胎儿和新生儿对缺氧的反应，如高原妇女、贫血患者、心脏病或肺病患者、脑血管血流改变伴脑出血和脑出血的患者。肺动脉高压，以及产妇应激机制和产前“编程”了解急性高山病、先兆子痫、高原脑和肺水肿的机制。