Collaborative Research: Physiological and regulatory mechanisms of the attenuation of maladaptive plasticity in highland deer mice

合作研究：高原鹿小鼠适应不良可塑性减弱的生理和调节机制

• 批准号: 1754503
• 负责人: Bridgett vonHoldt
• 金额: $ 13.51万
• 依托单位: Princeton University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-01 至 2021-04-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1754503&HistoricalAwards=false
• 关键词: Collaborative; Research; Physiological; regulatory; mechanisms

Many physiological systems buffer organisms against environmental perturbations by safeguarding their internal conditions against changes in the environment. Upon colonization of new environments, however, physiological systems that evolved in one environmental context may produce misdirected responses when they are inappropriately coopted to respond to novel challenges. Prominent examples of this phenomenon include several physiological responses to high-elevation environments in native lowlanders. For example, exposure to high elevation induces excessive red blood cell production, constriction of pulmonary blood vessels, and other physiological changes in lowlanders that may be considered maladaptive because they contribute to high-altitude diseases (e.g. chronic mountain sickness, pulmonary edema). In such cases, natural selection should favor attenuation of these maladaptive responses. This research focuses on understanding the evolutionary, physiological, and genetic mechanisms that allow such maladaptive ancestral responses to blunted, without simultaneously impacting beneficial responses. The project PIs will use a series of acclimation experiments and field studies of high- and low-altitude populations of deer mice to explore the adaptive modification of physiological responses to high-altitude stressors. Like indigenous high-elevation human populations, highland deer mice exhibit blunted maladaptive responses to hypoxia. The results of this research will also be used to develop a public outreach program that illustrates the value of comparative physiology for informing applied problems in human health using high-altitude environments and the animals that inhabit them as its centerpiece. These outreach efforts will be centered on the development of short films that will serve as springboards for interactive discussions between researchers and the general public.Many physiological responses to hypoxia are largely coordinated by a family of master transcription factors, known as hypoxia-inducible factors (HIF1-3). Because mutations that alter the function of transcription factors like HIF (i.e. trans-regulatory mutations) are prone to pleiotropic effects, evolutionary theory suggests that they should be rare in the adaptive modification of regulatory networks compared to changes that are more modular in their phenotypic effects. Nonetheless, recent genomic studies of high-elevation human populations, and several other species have shown that allelic variation in a gene (EPAS1) that encodes a specific HIF isoform (HIF2) has been the target of natural selection, and is associated with the attenuation of maladaptive responses to hypoxia. Thus, adaptive modification of regulatory networks that coordinate hypoxia responses seems to have repeatedly proceeded through modification of trans-regulatory factors in high-elevation specialists. This poses interesting physiological and evolutionary questions because HIF2 also coordinates a number of beneficial physiological changes to maintain O2 homeostasis. Given that alteration of HIF2 induce deleterious pleiotropic effects, how can maladaptive responses be attenuated while adaptive responses are maintained? Does alteration of HIF function require compensatory cis-regulatory mutations in HIF targets that coordinate adaptive responses or can compensatory modifications be achieved through epigenetic changes? This research will address these questions using a series of physiological, genetic, and transcriptomic experiments on highland and lowland deer mice. Like other highland specialists, patterns of allele frequency variation at EPAS1 suggest local adaptation in deer mice, and this variation is associated with the attenuation of maladaptive hypoxia responses.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

许多生理系统缓冲生物可以通过保护其内部条件抵抗环境的变化来防止环境扰动。然而，在新环境的殖民化后，在一种环境环境中进化的生理系统可能会在不适当地掌握应对新挑战时会产生误导的反应。这种现象的重要例子包括对本地低地人群高海拔环境的几种生理反应。例如，暴露于高升高会导致红细胞的过度产生，肺血管收缩以及低地人的其他生理变化，这些变化可能被认为是适应不良的，因为它们会导致高空疾病（例如，慢性山区疾病，肺部水肿）。在这种情况下，自然选择应有利于这些不良适应反应的衰减。这项研究重点是理解允许这种不良适应性祖先反应钝化的进化，生理和遗传机制，而不会同时影响有益反应。 PIS PIS将使用一系列的适应实验和鹿小鼠高海拔和低海拔种群的现场研究来探索生理反应对高空应激源的自适应修饰。像土著高海拔人群一样，高地鹿小鼠对缺氧的不良适应性反应钝。这项研究的结果还将用于制定公共外展计划，以说明比较生理学对使用高海拔环境和将其作为其核心居住的动物告知人类健康问题的价值。这些外展工作将集中在短片的发展上，这些短片将作为研究人员与公众之间的互动讨论的跳板。对缺氧的许多生理反应在很大程度上由一个主转录因子家族（称为低氧诱导因素）进行了协调（HIF1-3）。由于改变HIF（即反式调节突变）等转录因子功能的突变易于进行多效效应，因此进化理论表明，与更模块化的表型效应更模块化的变化相比，在调节网络的适应性修饰中，它们应该很少见。尽管如此，对高海拔人群的最新基因组研究以及其他几种物种表明，编码特定HIF同工型（HIF2）的基因（EPAS1）中的等位基因变异已成为自然选择的靶标，并且与对低氧不良反应不良反应的衰减有关。因此，通过在高海拔专家中修改跨调节因素的修改，对协调缺氧反应的调节网络的适应性修改似乎反复进行。这提出了有趣的生理和进化问题，因为HIF2还协调了许多有益的生理变化以维持O2稳态。鉴于HIF2的改变会引起有害的多效性影响，因此在保持自适应反应时如何减弱适应不良的反应？ HIF功能的改变是否需要在协调适应性反应的HIF靶标中进行补偿性顺式调节突变，或者可以通过表观遗传变化实现补偿性修改？这项研究将使用高地和低地鹿小鼠的一系列生理，遗传和转录组实验来解决这些问题。像其他高地专家一样，EPAS1等位基因频率变化的模式表明鹿小鼠的局部适应性，这种变化与适应性低氧缺氧反应的衰减有关。该奖项反映了NSF的法定任务，并认为通过基金会的知识分子和更广泛的影响，可以通过评估来进行评估。