Adaptation and acclimatization to high altitude in rodents.

啮齿动物对高海拔的适应和适应。

• 批准号: RGPIN-2019-06495
• 负责人: Joseph, Vincent
• 金额: $ 2.4万
• 依托单位: Université Laval
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=761990
• 关键词: Adaptation; acclimatization; altitude; rodents.

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.

生活在高海拔地区的哺乳动物具有增强O2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，并引入了新的哺乳动物物种HA。对其中大多数人来说，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，而大鼠仍然是唯一的低地物种。根据将小鼠起源于亚洲高山的地理历史，我们提出小鼠对HA是“预适应的”。在过去的几年里，我们描述了小鼠这些适应的生理基础：通气量和代谢率升高、交换表面积大的大肺以及HA肺部线粒体氧化应激水平低。初步结果表明，在慢性低氧习服3周期间，小鼠能够提高其每分钟通气量和代谢率，并显示脑线粒体呼吸的动态变化，而这些反应在大鼠中明显减弱。从长远来看，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。本提案中开发的短期研究问题将测试以下假设：-适应慢性缺氧涉及脑和肝脏中线粒体功能和代谢途径的可塑性（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O2消耗的比率），关键代谢酶的活性，以及与缺氧和代谢反应相关的线粒体呼吸和转录因子调节剂的表达。 - 由于性别对HA的适应具有主导作用，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，因此我们的第二个目标将是测试以下假设：在慢性缺氧的适应过程中，线粒体呼吸效率和代谢途径的可塑性在成年和新生动物中具有性别特异性。从长远来看，我们将评估卵巢激素及其受体对HA适应的作用。- HA居住地（拉巴斯，玻利维亚）改变新生和成年大鼠和小鼠脑和肝脏中的线粒体呼吸效率。我们将与来自玻利维亚的拉巴斯的同事合作，在3,600米处解决这个假设。 这些研究为学生提供了丰富和刺激的挑战，他们将不得不使用最先进的设备执行要求苛刻的技术方法，并了解他们的数据如何适合这个迷人的研究领域。