Collaborative Research: Role of endogenous carbon monoxide (CO) in hypoxia tolerant species

通常，一氧化碳（CO）被认为是一种严格意义上的有毒气体，但一氧化碳也会在人体中由血红素分解自然产生，血红素是红细胞中主要携带氧气的蛋白质（血红蛋白）的关键成分。研究小组的成员最近发现，某些深潜海豹的血液中含有中等高浓度的CO（与重度吸烟者的测量值相似）。目前，这些是已知的唯一一种自然产生如此高水平CO的物种，这可能会对经历低氧或血流量减少的组织产生强烈的保护作用，就像潜水时经常发生的那样。该项目验证了深潜海豹产生更高浓度的CO作为一种潜在的适应机制，以避免与它们的极端潜水行为相关的伤害的假设。它将调查血液中CO含量高的来源，CO的产生是如何被调节的，以及几种呼吸式潜水员血液和组织中CO浓度的范围。将进一步检查显示产生高浓度一氧化碳的物种，以评估与该气体有关的潜在保护特性。该研究具有潜在的应用价值，可以帮助减少人体再灌注损伤（例如，由于中风）。该项目是一个高度协作的项目，包括三名早期职业研究者，两名女科学家，一名博士后研究员，以及几名研究生和本科生。几项公共教育和推广活动已经计划好了，包括为加州阿诺纽沃州立保护区的公共教育捐款。内源性气体分子对生理过程调节的影响是生物学研究的一个迅速发展的领域。然而，这些分子与它们的生物靶点之间的相互作用，以及它们在野生动物中发挥的适应性作用，目前尚不清楚。该项目研究了潜水哺乳动物在缺氧和/或缺血时产生一氧化碳的遗传和生理机制，以及这种气体引发细胞保护作用的潜力。该项目验证了一种假设，即较高的CO浓度是由血红蛋白储存的增加和红细胞寿命短导致的这些储存的高周转率造成的。它还将测试CO是否对潜水物种有有益的影响，包括细胞保护、增加血红蛋白-氧亲和力和改变线粒体功能。这项研究的结果将促进对缺氧耐受性的生理适应的理解（例如，在潜水、高海拔或穴居物种中）。该合作项目支持3名早期职业研究者，并促进6个机构的1名博士后研究员、4名研究生和20多名本科生的研究培训和教育。本研究的结果将被纳入研究者讲授的课程中。该项目的更广泛影响包括让代表性不足的少数群体参与，加强六个机构的研究和教育基础设施，以及广泛传播研究和教育材料，以加强公众对关键科学概念的理解。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。

Often, carbon monoxide (CO) is thought of as a strictly toxic gas, but CO is also naturally produced in the body from the breakdown of heme, a key component of the primary oxygen-carrying protein (hemoglobin) found in red blood cells. Members of the research team recently discovered that certain species of deep-diving seals have moderately high concentrations of CO in their blood (similar to those measured in heavy cigarette smokers). Currently, these are the only species known to naturally produce such high levels of CO, which may elicit strong protective effects on tissues that experience low oxygen or reduced blood flow, as regularly occurs during diving. This project tests the hypothesis that deep-diving seals produce higher concentrations of CO as a potential adaptive mechanism to avoid injuries associated with their extreme diving behaviors. It will investigate the source of the high CO levels in the blood, how the production of CO is regulated, and the range of CO concentrations in blood and tissues from several species of air-breathing divers. Species shown to produce high concentrations of CO will be further examined to evaluate the potential protective properties associated with the gas. The research has potential applications that could assist in minimizing human reperfusion injuries (e.g., as a result of a stroke). The project is highly collaborative and includes three Early-Career Investigators, two female scientists, one post-doctoral researcher, and several graduate and undergraduate students. Several public education and outreach activities are planned, including contributions to public education at Ano Nuevo State Reserve in California.The impact of endogenously produced gas molecules on the regulation of physiological processes is a rapidly expanding area of biological research. However, the interactions between these molecules and their biological targets, and the adaptive roles they play in wildlife, are currently unknown. This project investigates the genetic and physiological mechanisms driving CO production and the potential for the gas to elicit cytoprotective effects during hypoxia and/or ischemia in diving mammals. The project tests the hypothesis that higher CO concentrations result from elevated heme-protein stores and a high turnover rate of these stores via short erythrocyte lifespans. It will also test whether CO has beneficial effects in diving species, including cytoprotection, increased hemoglobin-oxygen affinity, and altered mitochondrial function. The results from this study will advance understanding of physiological adaptations for hypoxia tolerance (e.g., in diving, high-altitude, or burrowing species). This collaborative project supports three Early-Career Investigators and promotes research training and education for one post-doctoral researcher, four graduate students, and over 20 undergraduates across six institutions. Results from this study will be incorporated into courses taught by the investigators. Broader Impacts of the project include participation of underrepresented minority groups, enhanced infrastructure for research and education at six institutions, and broad dissemination of research and educational materials to enhance public understanding of key scientific concepts.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.