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

合作研究：内源一氧化碳 (CO) 在耐缺氧物种中的作用

• 批准号: 1929325
• 负责人: ellen breen
• 金额: $ 15.13万
• 依托单位: University of California-San Diego
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-15 至 2023-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1929325&HistoricalAwards=false
• 关键词: Collaborative; Research; Role; endogenous; carbon

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.

通常，一氧化碳(CO)被认为是一种严格的有毒气体，但一氧化碳也是在体内由血红素分解而自然产生的，血红素是红细胞中主要携氧蛋白(血红蛋白)的关键成分。研究小组的成员最近发现，某些种类的深潜海豹血液中的一氧化碳浓度中等偏高(与重度吸烟者的测量结果相似)。目前，这些物种是已知的唯一天然产生如此高水平一氧化碳的物种，这可能会对经历低氧或血液流动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。该项目验证了一种假设，即深潜海豹产生更高浓度的一氧化碳，作为一种潜在的适应机制，以避免与其极端潜水行为相关的伤害。它将调查血液中高水平一氧化碳的来源，一氧化碳的产生是如何调节的，以及几种呼吸空气的潜水员血液和组织中一氧化碳浓度的范围。将进一步检查被证明会产生高浓度CO的物种，以评估与这种气体相关的潜在保护性能。这项研究具有潜在的应用价值，可能有助于将人类再灌注损伤降至最低(例如，由于中风)。该项目具有高度的协作性，包括三名职业生涯早期的研究人员、两名女科学家、一名博士后研究人员以及几名研究生和本科生。计划了几项公共教育和推广活动，包括为加利福尼亚州阿诺新沃州立保护区的公共教育做出贡献。内源性产生的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扩大的领域。然而，这些分子与它们的生物靶标之间的相互作用，以及它们在野生动物中扮演的适应性角色，目前尚不清楚。本项目研究了潜水哺乳动物体内CO产生的遗传和生理机制，以及GAS在缺氧和/或缺血期间诱导细胞保护作用的可能性。该项目测试了一种假设，即更高的CO浓度是由于血红素蛋白储存的增加和这些储存的高周转率通过较短的红细胞寿命而产生的。它还将测试一氧化碳是否对潜水物种有好处，包括细胞保护、增加血红蛋白与氧气的亲和力和改变线粒体功能。这项研究的结果将促进对耐低氧的生理适应的理解(例如，在潜水、高海拔或穴居物种中)。该合作项目支持三名早期职业研究人员，并促进六个机构的一名博士后研究人员、四名研究生和20多名本科生的研究培训和教育。这项研究的结果将被纳入调查人员教授的课程。该项目的更广泛影响包括代表不足的少数群体的参与，六个机构加强研究和教育的基础设施，以及广泛传播研究和教育材料以增强公众对关键科学概念的理解。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。