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

生理可塑性和适应缺氧的机制：利用野鹿小鼠的自然变异

• 批准号: 10501253
• 负责人: Jonathan Paul Velotta
• 金额: $ 32.56万
• 依托单位: UNIVERSITY OF DENVER (COLORADO SEMINARY)
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10501253
• 关键词: Acute; Altitude; Altitude Sickness; American; Animals; Biology; Blood Viscosity; Cerebrovascular Disorders; Cessation of life; Chronic; Coupled; Deer Mouse; Disease; Exposure to; Functional disorder; Genetic; Genomics; Health; Heart; Heart Diseases; Heart failure; Homeostasis; Human; Hypoxia; Laboratories; Lead; Lung; Lung diseases; Maintenance; Medicine; Modeling; Molecular; Natural Selections; Network-based; North America; Oxygen; Pathology; Peromyscus; Persons; Physiological; Physiology; Population; Pregnancy Outcome; Process; Quantitative Genetics; Regulatory Pathway; Resources; Series; Testing; Time; Variant; experimental study; field study; genetic architecture; human disease; insight; meter; new therapeutic target; response; trait; transcriptome sequencing; transcriptomics

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.

项目概要 维持 O2 稳态是人类健康的重要组成部分。它的破坏，对于 例如，有助于许多毁灭性疾病的病理生理学，包括心脏病、 肺、脑血管疾病。此外，环境氧气的普遍减少 高海拔地区的可用性对全世界越来越多的人构成严重威胁 生活在2500米以上的。例如，长期处于高原缺氧状态会导致 慢性疾病，如慢性高山病，以及阴性妊娠 结果，心力衰竭甚至死亡。这是因为在慢性条件下 环境缺氧，旨在维持体内平衡的几种生理反应 急性缺氧条件下可导致肺适应不良重塑 血管系统和血液粘度增加，可能使心脏负担过重。在 Velotta 实验室中， 我们以野生高海拔鹿鼠（Peromyscus maniculatus）为模型来了解 综合进化机制使动物能够克服这些挑战。鹿 小鼠是一个非常适合的模型：它们广泛分布在海拔超过 4000 米的地区 北美洲，很容易在野外捕获并在实验室中进行操作，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 高海拔生理学。我们将首次使用定量遗传学来识别基因座 这是对缺氧的生理反应的适应性变化的基础，加上详细的RNA- 测序和基于网络的转录组学方法来识别调控途径 这些反应的基础。结合这些方法使我们能够查明遗传 高海拔地区进化的生理变化的结构。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 在适应这些极端的过程中，自然选择对生理特征的强度 状况。该提案中概述的大规模且雄心勃勃的一系列实验将 对高海拔生物学和医学产生新的见解，并可能带来新的治疗方法 O2 稳态破坏是其病理学核心的疾病的目标。