(INTRODUCTION) MECHANISMS OF ACCLIMATIZATION: FETUS AND ADULT

描述(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低氧(LTH)的基本机制。此外，我们将研究这些机制与从胎儿到成人的发育有关。这一应用是一个基础广泛的多学科综合计划，使用生理学、药理学、细胞学、生化和分子方法。基于我们团队21年的研究，我们将在适应高海拔(3801米/12,470英尺)的绵羊上进行研究。我们将检验一些假说。总体假设是，高海拔LTH导致母亲和胎儿全身、细胞和亚细胞反应的协调，显著影响发育可塑性和随后的疾病风险。在脑动脉中，我们将测试有关钙肾上腺素能介导的钙依赖和钙非依赖性调控细肌丝和粗肌丝的信号转导机制的假说，例如，阿尔法肾上腺素能受体亚型、蛋白激酶C亚型、细胞外信号调节激酶的作用以及与下游效应器的偶联。我们将验证低氧习服对动脉结构和功能的影响是由血管内皮生长因子及其对胎儿大脑动脉的平滑肌、内皮和血管周围神经的影响所介导的假说。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，我们将研究类固醇激素的机制 妊娠期LTH致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，它们还将阐明成熟发展的一些方面。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，它们与对长期低氧的反应有关，如生活在高海拔地区的妇女，以及吸烟或贫血、患有心脏病或肺病或“胎盘功能不全”的妇女。对于新生儿，它们与脑内出血和肺动脉高压的脑血管血流改变有关。2)这些研究还将有助于理解母体心血管疾病的机制和对成人疾病的产前“规划”。3)最后，这些研究有助于了解疾病的发病机制，包括：急性高原反应、先兆子痫、高原脑和肺水肿。 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，这些研究涉及以下重要问题：胎儿和新生儿对低氧的反应，如高原妇女，以及贫血、心脏病或肺部疾病、脑血管血流改变并伴有脑出血和肺动脉高压的人，以及母亲应激的机制和产前“编程”了解急性高原反应、先兆子痫以及高原脑和肺水肿的机制。

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.