Respiratory and genomic contributions to adaptive/maladaptive hypoxia responses

项目摘要/摘要 有效利用氧气的能力是生存所必需的。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 处于氧平衡状态。高海拔地区的人口受到了低氧的挑战。 数百代人，并表现出对这一现象的独特生理反应 环境胁迫与氧气相关基因的极强自然选择 运输，这可以在相对较小的研究中得到证明。例如，我们是第一个 阐明缺氧诱导因子(HIF)途径中基因之间的关系 在自然选择和相对较低的血红蛋白浓度下，这进一步 在藏族人中，与运动能力有关。在这里，我们提出了类似的综合和 有针对性地确定适应性和适应性不良的遗传决定因素 安第斯原住民对缺氧的心肺反应，他们表现出广泛的 心肺表型，包括藏族罕见的慢性高原病(CMS)。 CMS的特点是红细胞增多，动脉血氧分压低，二氧化碳滞留， 和迟钝的呼吸性化学反射，这也是与不良预后相关的特征 患有慢性心肺疾病的患者。我们建议检验一下最重要的假设 心肺表型(血红蛋白浓度、动脉血流量)的个体差异 血氧饱和度、低氧/高碳酸血症、呼吸和心血管反应 通过(1)缺乏适应性变异和/或(2)在确定的基因座上改变表观遗传调节 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。 我们还将检验睡眠呼吸暂停的严重程度是表观遗传变化的原因这一假设。 进一步改变心肺反应，就像先前在动物研究中所证明的那样 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获得- 或功能丧失寻求治疗方案以减轻对低氧的不良适应反应 在海平面上患有慢性心肺疾病的患者。

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.