Respiratory and genomic contributions to adaptive/maladaptive hypoxia responses

项目概要/摘要 有效利用氧气的能力对生存至关重要。许多重大的人类疾病， 包括心肺疾病、高血压、睡眠呼吸暂停和癌症， 氧气平衡高海拔地区的人类面临着缺氧的挑战 并显示出独特的生理反应 环境压力和与氧有关的基因的极强的自然选择 运输，这可以在相对较小的研究中证明。例如，我们是第一个 证明缺氧诱导因子（HIF）通路中基因之间的关系， 在自然选择和相对较低的血红蛋白浓度下， 与运动能力相关的疾病。在这里，我们提出了一个类似的综合和 有针对性的方法，以确定适应性和适应不良的遗传决定因素 安第斯土著人对缺氧的心肺反应，他们表现出广泛的 心肺表型，包括慢性高原病（CMS）罕见的藏族。 CMS的特征是红细胞过多，动脉血氧不足，二氧化碳潴留， 和迟钝的反射性化学反射，这也是与不良结果相关的特征， 慢性心肺疾病患者。我们打算检验这个总体假设 心肺表型的个体差异（血红蛋白浓度，动脉 氧饱和度、低氧/高碳酸血症和心血管反应）进行预测 通过（1）缺乏适应性变体和/或（2）在鉴定为 对患有和不患有CMS的安第斯男性和女性进行强大的最先进的基因组分析。 我们也将检验睡眠呼吸暂停的严重程度是表观遗传变化的基础这一假设 如先前在动物研究中所证实的， 间歇性缺氧最后，我们将确定遗传和表观遗传变异是否会导致增益- 或功能丧失，以寻求减轻对缺氧的适应不良反应的治疗选择 慢性心脏病和肺病的患者。

Project Summary/Abstract The ability to use oxygen effectively is essential for survival. Many significant human diseases, including cardiopulmonary disease, hypertension, sleep apnea, and cancer involve a disruption in oxygen homeostasis. Human populations at high altitude have been challenged by hypoxia for hundreds of generations and show both unique physiological responses to this environmental stress and extremely strong natural selection for genes involved in oxygen transport, which can be demonstrated in relatively small studies. For example, we were the first to demonstrate a relationship between genes in the hypoxia inducible factor (HIF) pathway under natural selection and relatively lower hemoglobin concentration, which is further associated with exercise capacity, in Tibetans. Here we propose a similar integrative and targeted approach to identify the genetic determinants of both adaptive and maladaptive cardiopulmonary responses to hypoxia in Andean natives, who show a wide range of cardiorespiratory phenotypes, including chronic mountain sickness (CMS) rare among Tibetans. CMS is characterized by excessive erythrocytosis, arterial hypoxemia, carbon dioxide retention, and blunted ventilatory chemoreflexes, which are also traits associated with poor outcomes in patients with chronic heart and lung disease. We propose to test the overarching hypothesis that individual differences in cardiopulmonary phenotypes (hemoglobin concentration, arterial oxygen saturation, hypoxic/hypercapnic ventilatory and cardiovascular responses) are predicted by (1) a lack of adaptive variants and/or (2) altered epigenetic regulation at loci identified with powerful state-of-the-art genomic analyses of Andean men and women with and without CMS. We will also test the hypothesis that the severity of sleep apnea underlies epigenetic changes that further modify cardiopulmonary responses as previously demonstrated in animal studies of intermittent hypoxia. Finally, we will determine if genetic and epigenetic variants result in gain- or loss-of-function to pursue therapeutic options for mitigating maladaptive responses to hypoxia in patients at sea level with chronic heart and lung disease.