The Neurobiology of Hypoxia Tolerance in the Naked Mole-Rat

该项目将通过研究非洲裸鼹鼠，有助于了解神经系统对缺氧（低氧水平）的耐受性。这种哺乳动物生活在拥挤、缺氧的洞穴中，并进化出了在长时间缺氧的情况下生存而不引发脑细胞死亡的能力。这个项目将测试新的目标基因，这些基因可能会保护脑细胞免受缺氧造成的细胞死亡，并有可能应用于设计新的治疗方法，用于治疗中风或心脏病发作等创伤性事件中缺氧的人类。通过研究裸鼹鼠的基因组，研究人员先前发现了该物种基因的变化，这些变化可能会减少因缺氧而导致的细胞死亡。当前项目的目标是测试这些基因在脑细胞保护中的潜在作用。该项目每年将资助两名研究生，他们将帮助指导从现有项目中招募的一些本科生研究人员，这些项目的目标是来自科学领域代表性不足的群体的学生。有关裸鼹鼠的信息将通过与当地动物园和地区高中的联系分享。该项目将研究大脑中缺氧耐受性的分子、细胞和生理机制，并将有助于理解对环境挑战的进化适应。裸鼹鼠将成为研究哺乳动物大脑缺氧耐受的分子和遗传基础的模型系统。与大多数其他哺乳动物相比，裸鼹鼠的脑细胞表现出对缺氧的内在耐受性，并且在缺氧期间钙积累的急剧减少，这可能是由于多种适应限制和缓冲钙电流的结果。此外，在裸鼹鼠的大脑中，内源性大麻素系统似乎具有重要的神经保护作用。本项目将专门研究钙通道TRPM7、NMDA谷氨酸受体离子通道、钙相关激酶、钙结合蛋白parvalbumin以及内源性大麻素系统的神经保护功能。研究人员将使用脑切片电生理学、质谱分析和基因操作技术来确定裸鼹鼠耐缺氧的分子和遗传基础。旨在将裸鼹鼠特有的基因改变引入小鼠细胞的实验将验证裸鼹鼠基因的变化也可以保护其他物种的假设。了解脑细胞是如何免受缺氧保护的，可能最终为心脏病发作和中风患者带来新的治疗靶点。几名研究生和本科生实习生将参与研究，研究结果将纳入本科课程和推广活动。该奖项由BIO-IOS的生理机制和生物力学项目以及神经系统集群组织项目共同资助。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

This project will contribute to understanding tolerance of hypoxia (low oxygen levels) within the nervous system by studying the African naked mole-rat. This mammal lives in crowded, oxygen-starved burrows, and has evolved the ability to survive extended periods of oxygen deprivation without triggering brain cell death. This project will test new target genes that may protect brain cells from cell death resulting from exposure to hypoxia, with potential applications in designing new treatments for humans that experience oxygen deprivation during traumatic events like a stroke or heart attack. By studying the genome of the naked mole-rat, the investigators previously discovered changes in the genes of this species that likely reduce cell death from oxygen deprivation. The goal of the current project is to test each of those genes for its potential role in brain cell protection. The project will support two graduate students each year, who will help mentor a number of undergraduate student researchers recruited from existing programs targeting students from groups underrepresented in science. Information on the naked mole-rat will be shared via outreach to a local zoo and area high schools. This project will investigate molecular, cellular, and physiological mechanisms in the brain that underly hypoxia tolerance and will contribute to understanding evolutionary adaptations to environmental challenges in general. The naked mole-rat will be developed as a model system for studying the molecular and genetic basis of hypoxia tolerance in the mammalian brain. Brain cells from the naked mole-rat display an intrinsic tolerance to hypoxia and a dramatic reduction in calcium accumulation during hypoxia compared with most other mammals, which is hypothesized to result from multiple adaptations that limit and buffer calcium currents. Additionally, there appears to be a significant neuroprotective role for the endocannabinoid system in the brain of the naked mole-rat. This project will specifically examine the neuroprotective function of the calcium channel TRPM7, NMDA glutamate-receptor ion channels, a calcium-related kinase, and the calcium-binding protein parvalbumin, as well as the endocannabinoid system. The investigators will use brain slice electrophysiology, mass spectrometry, and gene manipulation techniques to determine the molecular and genetic basis of hypoxia tolerance in the naked mole-rat. Experiments designed to introduce naked mole-rat-specific gene alterations into mouse cells will test the hypothesis that the changes in the naked mole-rat genes can also protect other species. Understanding how brain cells are protected from oxygen deprivation may ultimately lead to new therapeutic targets for heart attack and stroke victims. Several graduate and undergraduate student trainees will participate in the research, and results will be incorporated into undergraduate courses and outreach activities.This award was co-funded by the Physiological Mechanisms and Biomechanics Program and the Neural Systems Cluster Organization Program in BIO-IOS.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.