Adaptation and acclimatization to high altitude in rodents.

生活在高海拔地区的哺乳动物具有增强氧气运输和利用的遗传适应性。在过去的几个世纪里，低地人类移民建立了新的定居点，并向HA引入了新的哺乳动物物种。对这些人口中的大多数来说，适应是一个持续的过程，取得的成功各不相同。例如，在过去的几个世纪里，大鼠和小鼠都被引入南美洲，但只有小鼠在HA地区定居，而大鼠仍然是一个专门的低地物种。根据将小鼠的起源置于亚洲高山脉附近的系统地理学历史，我们提出小鼠“预先适应”了HA。在过去的几年中，我们描述了小鼠这些适应性的生理基础：高通气和代谢率，大交换表面积的大肺，以及HA时肺部线粒体氧化应激水平低。初步结果表明，在适应慢性缺氧3周的过程中，小鼠的微小通气量和代谢率升高，脑线粒体呼吸出现动态变化，而大鼠的这些反应明显减弱。从长期来看，我的研究计划的目标是通过比较大鼠和小鼠对慢性缺氧的反应，更好地了解适应和预适应高海拔的生理和细胞基础。本提案中提出的短期研究问题将验证以下假设：-慢性缺氧的适应涉及线粒体功能和脑和肝脏代谢途径的可塑性（占小鼠基础代谢率的50%）。我们将评估线粒体呼吸效率（通过测量ATP产生与氧气消耗的比例）、关键代谢酶的活性、线粒体呼吸调节剂的表达以及与缺氧和代谢反应相关的转录因子。-由于性别对HA的适应有主要影响，并且性类固醇调节成年和新生哺乳动物的线粒体呼吸和代谢功能，我们的第二个目标将是验证在适应慢性缺氧过程中线粒体呼吸效率和代谢途径的可塑性在成人和新生儿中具有性别特异性的假设。从长远来看，我们将评估卵巢激素及其受体对血凝素适应的作用。- HA居住（玻利维亚拉巴斯）改变新生儿和成年大鼠和小鼠大脑和肝脏的线粒体呼吸效率。我们将与来自海拔3600米的玻利维亚拉巴斯的同事合作，来验证这一假设。这些研究为学生提供了丰富而刺激的挑战，他们将不得不使用最先进的设备执行苛刻的技术方法，并了解他们的数据如何适合这个迷人的研究领域。

Mammals living at high altitude (HA) have genetic adaptations to enhance transport and utilization of O2. Over the past centuries, lowland human migrants have established new settlements and introduced new mammalian species to HA. For most of these populations adaptation is an ongoing process, with divergent successes. As an example, rats and mice have both been introduced in South America in the past centuries, but only mice have colonized the HA regions, while rats remain exclusively a lowland species. In line with the phylogeographic history placing the origin of mice around the high-mountain ranges of Asia, we proposed that mice are "pre-adapted" to HA. Over the past few years, we have described the physiological basis underlying these adaptations in mice: elevated ventilation and metabolic rate, large lungs with large exchange surface area, and low levels of mitochondrial oxidative stress in the lungs at HA. Preliminary results indicate that during acclimatization to chronic hypoxia for 3 weeks, mice are able to elevate their minute ventilation and metabolic rate, and show dynamic changes of brain mitochondrial respiration, while these responses are clearly blunted in rats. On the long term, the objectives of my research program are to better understand the physiological and cellular basis of adaptation and pre-adaptation to high altitude by comparing responses to chronic hypoxia in rats and mice. Short-term research questions developed in this proposal will test the following hypothesis: - acclimatization to chronic hypoxia involves plasticity of mitochondrial function and metabolic pathways in the brain and liver (that account for 50% of basal metabolic rate in mice). We will assess mitochondrial respiration efficiency (by measuring the ratio of ATP production to O2 consumption), the activity of key metabolic enzymes, and expression of modulators of mitochondrial respiration and transcription factors related to hypoxic and metabolic responses. - Because sex has a predominant effect on acclimatization to HA, and sex-steroids modulate mitochondrial respiration and metabolic functions in adult and newborn mammals, our second objective will be to test the hypothesis that plasticity of mitochondrial respiration efficiency and metabolic pathways during acclimatization to chronic hypoxia are sex-specific in adults and in newborn. On the long term, we will assess the role of ovarian hormones and their receptors on HA adaptations. - HA residency (La Paz, Bolivia) alters mitochondrial respiration efficiency in the brain and liver of newborn and adults rats and mice. We will work with our colleagues from La Paz, Bolivia, at 3,600m to address this hypothesis. These studies provide rich and stimulating challenges for students, who will have to perform demanding technical approaches with state-of the art equipment and understand how their data fits into this fascinating field of research.