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: 1927675
• 负责人: Jay Storz
• 金额: $ 9.75万
• 依托单位: University of Nebraska-Lincoln
• 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 2022-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1927675&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CO也是体内血红素分解时自然产生的，血红素是红细胞中主要载氧蛋白（血红蛋白）的关键成分。研究小组成员最近发现，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，这些是已知的唯一自然产生如此高水平的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，就像潜水期间经常发生的那样。该项目测试的假设，深潜海豹产生更高浓度的CO作为一个潜在的适应机制，以避免与他们的极端潜水行为相关的伤害。它将调查血液中高CO水平的来源，CO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CO浓度的范围。将进一步检查产生高浓度CO的物种，以评估与气体相关的潜在保护特性。该研究具有潜在的应用，可以帮助最大限度地减少人类再灌注损伤（例如，作为中风的结果）。该项目是高度合作的，包括三个早期职业调查员，两名女科学家，一名博士后研究员，以及几个研究生和本科生。计划开展几项公共教育和外联活动，包括为加州的阿诺努埃沃州保留地的公共教育作出贡献。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展的领域。然而，这些分子与其生物靶标之间的相互作用，以及它们在野生动物中发挥的适应性作用，目前尚不清楚。该项目研究了驱动CO产生的遗传和生理机制，以及气体在潜水哺乳动物缺氧和/或缺血期间引起细胞保护作用的潜力。该项目测试的假设，较高的CO浓度导致血红素蛋白储存升高，这些商店通过短红细胞寿命的高周转率。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）。该合作项目支持三名早期职业调查员，并促进六所机构的一名博士后研究员，四名研究生和20多名本科生的研究培训和教育。这项研究的结果将纳入研究人员教授的课程。该项目的更广泛影响包括代表性不足的少数群体的参与，六个机构的研究和教育基础设施的加强，以及研究和教育材料的广泛传播，以提高公众对关键科学概念的理解。该奖项反映了NSF的法定使命，并被认为是值得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的支持。