(INTRODUCTION) MECHANISMS OF ACCLIMATIZATION: FETUS AND ADULT

描述（由申请人提供）：本次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，我们将研究这些与胎儿到成人发育有关的机制。这个应用是一个广泛的、多学科的综合程序，使用生理学、药理学、细胞、生化和分子方法。基于我们小组21年的研究，研究将在适应高海拔（3801米/ 12470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引起母体和胎儿的全身、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，我们将测试关于Ca^*依赖和Ca^*不依赖的薄肌和粗肌纤维调节的肾上腺素能介导的信号转导机制的假设，例如，α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，以及与下游效应物的偶联。我们将验证缺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，以及它对胎儿大脑动脉平滑肌、内皮和血管周围神经的影响。此外，我们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

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.