Physiological plasticity and the mechanisms of adaptation to hypoxia: exploiting natural variation in wild deer mice

项目总结 氧平衡的维持是人类健康的重要组成部分。它的颠覆，对于 例如，对许多毁灭性疾病的病理生理学有贡献，包括心脏， 肺、脑血管疾病。此外，环境中O2的普遍减少 高海拔地区的可获得性对全球日益增长的人口构成严重威胁 它们生活在2500米以上。例如，长期暴露在高海拔低氧环境中会导致 与慢性高山病等慢性疾病以及阴性妊娠有关 结果，心力衰竭甚至死亡。这是因为在慢性病的情况下 环境低氧，旨在维持内环境平衡的几种生理反应 在急性缺氧条件下可导致肺的不适应性重塑 血管系统和血液粘度的增加会使心脏不堪重负。在维洛塔实验室， 我们研究了野生的高海拔鹿鼠(Permyscus Manulatus)作为模型，以了解 使动物能够克服这些挑战的综合进化机制。鹿 老鼠是一个非常合适的模型：它们广泛分布在海拔4000米的 北美洲，很容易在野外捕获并在实验室中操纵，富含 生理和基因组资源，最重要的是，已经适应了进化 时间到了高海拔的极端条件。在接下来的五年里，我的实验室将剖析 自然选择重塑鹿鼠的遗传和分子机制 高海拔的生理学。我们将首次使用数量遗传学来鉴定这些基因座 这是低氧生理反应的适应性变化的基础，再加上详细的RNA- 以测序和网络为基础的转录切割方法来识别调控途径 这是这些回应的基础。结合这些方法使我们能够准确地定位基因 高海拔地区进化生理变化的构筑。最后，我们将使用我们的 了解潜在的遗传结构，以直接测试形式、方向和 在适应这些极端情况时，自然选择对生理性状的影响 条件。这项提案中概述的大规模和雄心勃勃的一系列实验将 对高原生物学和医学产生新的见解，并可能导致新的治疗方法 疾病的靶点，在这些疾病中，氧平衡的破坏是其病理的核心。

PROJECT SUMMARY The maintenance of O2 homeostasis is a critical component of human health. Its disruption, for example, contributes to the pathophysiology of many devastating diseases, including heart, lung, and cerebrovascular disease. In addition, pervasive reductions in environmental O2 availability at high altitudes pose a serious threat to the growing number of people worldwide that live above 2500 meters. For example, long-term exposure to high altitude hypoxia can lead to chronic conditions such as Chronic Mountain Sickness, as well as negative pregnancy outcomes, heart failure or even death. This is because under conditions of chronic environmental hypoxia, several physiological responses aimed at maintaining homeostasis under acute hypoxic conditions can lead to maladaptive remodeling of the pulmonary vasculature and increases in blood viscosity that can overburden the heart. In the Velotta lab, we study wild, high-altitude deer mice (Peromyscus maniculatus) as a model to understand the integrated evolutionary mechanisms that allow animals to overcome these challenges. Deer mice are a well-suited model: they are broadly distributed across > 4000 meters of elevation in North America, are easily captured in the wild and manipulated in the lab, are rich in physiological and genomic resources, and most importantly, have adapted over evolutionary time to the extreme conditions of high altitude. Over the next five years, my lab will dissect the genetic and molecular mechanisms by which natural selection has reshaped deer mouse physiology at high altitude. We will use quantitative genetics to identify, for the first time, the loci that underlie adaptive variation in physiological response to hypoxia, coupled with detailed RNA- sequencing and network-based transcriptomic approaches to identify the regulatory pathways that underlie such responses. Combining these approaches allows us to pinpoint the genetic architecture of evolved physiological change at high altitude. Finally, we will use our understanding of underlying genetic architecture to directly test for the form, direction, and strength of natural selection on physiological traits during adaptation to these extreme conditions. The large-scale and ambitious series of experiments outlined in this proposal will yield new insights into high-altitude biology and medicine and may lead to novel therapeutic targets for diseases in which the disruption of O2 homeostasis is central to their pathology.