MECHANISMS OF ACCLIMATIZATION; FETUS AND ADULT

这项建议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，我们还将研究与发展相关的几种机制。这项建议是一个基础广泛的，多学科的综合计划，使用生理学、药理学、细胞学、生化和分子方法。基于我们团队16年的研究，我们将在适应高海拔(3820米/12,470英尺)的绵羊身上进行研究。我们将检验一些假说。例如，在大脑动脉中，我们将测试关于钙(Ca~(2+))非依赖和钙~(2+)依赖的调控细肌丝和粗肌丝的信号转导机制的假设，例如，蛋白激酶C(PKC)、细胞外信号调节激酶(ERKs)、α肾上腺素能受体亚型的作用，偶联到第二 信使、Rho/Rho激酶、蛋白激酶G(PKG)和下游效应蛋白。我们将测试几个关于大脑和肺动脉血浆钙激活的K+通道，它们的磷酸化状态和/或剪接变体的假说。此外，我们还将探讨血管周围神经在调节脑血管反应性中的作用。在妊娠和非妊娠子宫动脉中，我们将研究LTH对PKC-ERK的调节机制以及相关的相互作用。最后，我们将探讨LTH如何改变胎儿下丘脑-垂体-肾上腺反应，包括下丘脑驱动、垂体 反应性和糖皮质激素的合成。从科学上讲，这些研究将增强我们对胎儿和成人适应慢性低氧的机制的理解。此外，他们还将阐明从胎儿到成人发育的许多方面。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，它们与长期缺氧有关，如生活在高海拔地区的妇女，以及吸烟或暴露在环境污染中的妇女，贫血或患有心脏病或肺部疾病的妇女，或“胎盘功能不全”的妇女。对于新生儿来说，它们与脑内出血和肺动脉高压的脑血管血流改变有关。2)这些研究也将有助于理解产前“程序设计”的机制。 成人疾病。3)最后，这些研究与了解成人和儿童疾病的机制有关，例如急性高原病、先兆子痫、高原脑和肺水肿。

The overall theme of this proposal is to explore fundamental mechanisms whereby the fetus and adult acclimatize to high altitude, long-term hypoxia (LTH). In addition, we will examine several of these mechanisms in association with development. This proposal is a broadly based, multidisciplinary, integrated program using physiologic, pharmacologic, cellular, biochemical, and molecular approaches. Based on >16 years of research by our group, studies will be conducted in sheep acclimatized to high altitude (3820 m/12,470 ft). We shall examine a number of hypotheses. For example, in cerebral arteries we will test hypotheses regarding signal transduction mechanisms for both calcium (Ca2+)-independent and Ca2+-dependent regulation of thin and thick myofilament, e.g., the roles of protein kinase C (PKC), extracellular signal regulated kinases (ERKs), alpha adrenergic receptor subtypes, coupling to second messengers, Rho/Rho kinase, protein kinase G (PKG), and downstream effector proteins. We will test several hypotheses in regards to cerebral and pulmonary artery plasmalemmal Ca2+-activated K+ channels, their phosphorylation states and/or splice variants. In addition, we will explore the role of perivascular nerves in regulating cerebrovascular reactivity. In pregnant and nonpregnant uterine arteries, we will examine mechanisms of LTH modulation of PKC-ERK and related interactions. Finally, we will explore how LTH alters fetal hypothalamic-pituitary-adrenal responses, including the role of hypothalamic drive, pituitary responsiveness, and glucocorticoid synthesis. Scientifically the studies will augment our understanding of mechanisms whereby the fetus and adult acclimatize to chronic hypoxia. In addition, they will shed light on a number of aspects of development from fetus to adult. From a clinical standpoint, these studies relate to at least three important problems. 1) For the fetus and newborn they relate to prolonged hypoxia as occurs in women who live at high altitude, as well as those who smoke or are exposed to environmental pollution, those who are anemic, or who have heart or lung disease, or with "placental insufficiency." For the newborn they relate to altered cerebrovascular blood flow with intracerebral hemorrhage and pulmonary hypertension. 2) The studies also will contribute to understanding mechanisms of prenatal "programming" of adult disease. 3) Finally, the studies are relevant to understanding mechanisms of diseases in adults and children, e.g., Acute Mountain Sickness, Preeclampsia, and High Altitude Cerebral and Pulmonary Edema.