Slowing the pace: Cellular and Molecular Mechanisms of Bradycardia in the Anoxic Turtle (Trachemys scripta)

放慢速度：缺氧龟（Trachemys scripta）心动过缓的细胞和分子机制

• 批准号: 1557818
• 负责人: Jonathan Stecyk
• 金额: $ 58万
• 依托单位: University of Alaska Anchorage Campus
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1557818&HistoricalAwards=false
• 关键词: Slowing; pace; Cellular; Molecular; Mechanisms

The vast majority of vertebrate species are unable to survive without access to oxygen. Death quickly ensues from oxygen lack due to the failure of organs, such as the heart, which require a constant supply of oxygen to create the metabolic energy necessary to support their continued function. However, in stark contrast to "normal" vertebrates, a few vertebrate species have evolved the remarkable ability to survive for prolonged periods in the complete absence of oxygen (termed anoxia). This research focuses on elucidating how the heart of one of the vertebrate champions of anoxia survival, the red-eared slider turtle (Trachemys scripta), can continue to beat rhythmically during anoxia, albeit more slowly. Previous research has revealed that the intrinsic rate at which the turtle heart beats is vastly slowed by anoxia exposure. However, the mechanisms that act to suppress the intrinsic heart rate during anoxia remain unknown. In the vertebrate heart, intrinsic heart rate is determined by cells located in a specialized region, termed the cardiac pacemaker. The pacemaker cells initiate cardiac contraction by producing electrical impulses, called pacemaker action potentials, the rate of which sets intrinsic heart rate. This research will utilize a multi-tiered and multidisciplinary approach to investigate the physiological mechanisms by which anoxia and low temperature modulates pacemaker rate. Ultimately, by probing how a vertebrate heart can continue to beat in the absence of oxygen, this research will develop a deeper understanding of the connections between oxygen, metabolism and electrical excitation, which are a crucial aspect of basic cardiac biology. In addition, the intimate intertwining of research activities with training, education and mentoring opportunities in contemporary physiology and cell biology for students at UAA as well as those of the broader Alaskan community will broaden exposure and enhance opportunity in scientific research for individuals that are underrepresented in STEM disciplines.Remarkably, the heart of one of the vertebrate champions of anoxia survival, the red-eared slider turtle (Trachemys scripta) can continue to beat rhythmically during anoxia, albeit more slowly. Previous research has revealed that a dramatic and rapid resetting of the intrinsic pacemaker contributes to the bradycardia displayed by the anoxic turtle. However, the mechanism by which anoxia modulates pacemaker rate remains unknown. The overarching objective of this research is to exploit the turtle heart as a model to elucidate the physiological and cellular mechanisms of cardiac pacemaker regulation. This research will utilize a multi-tiered and multidisciplinary approach to systematically investigate in the organ (contractile properties of isolated heart chambers; in vitro recordings of pacemaker action potentials) and cell (electrophysiological measures of ionic currents in isolated cardiomyocytes) the alterations of the cardiac pacemaker that underlies the resetting of intrinsic heart rate by anoxia. The proposed research will provide important insights into the molecular mechanisms of cardiac pacemaking in conditions of low oxygen and temperature. Both have pertinence to basic cardiac biology as well as human pathology, and the anoxic turtle provides a remarkable model of how these processes persist in conditions of substantial stress.

绝大多数脊椎动物物种在没有氧气的情况下无法生存。 由于器官（如心脏）的衰竭而导致的缺氧会很快导致死亡，心脏需要持续的氧气供应来产生支持其持续功能所必需的代谢能量。然而，与“正常”脊椎动物形成鲜明对比的是，一些脊椎动物物种已经进化出在完全没有氧气（称为缺氧）的情况下长时间生存的显着能力。这项研究的重点是阐明缺氧生存的脊椎动物冠军之一，红耳滑龟（Trachemys scripta）的心脏如何在缺氧期间继续有节奏地跳动，尽管更慢。 先前的研究表明，海龟心脏跳动的内在速率因缺氧而大大减慢。然而，在缺氧期间抑制固有心率的机制仍然未知。在脊椎动物心脏中，固有心率由位于称为心脏起搏器的专门区域中的细胞决定。起搏细胞通过产生电脉冲（称为起搏动作电位）启动心脏收缩，其速率决定固有心率。本研究将采用多层次和多学科的方法来研究缺氧和低温调节起搏器频率的生理机制。 最终，通过探索脊椎动物心脏如何在缺氧的情况下继续跳动，这项研究将更深入地了解氧气，代谢和电兴奋之间的联系，这是基础心脏生物学的一个重要方面。此外，研究活动与UAA学生以及更广泛的阿拉斯加社区学生在当代生理学和细胞生物学方面的培训，教育和指导机会紧密交织在一起，这将扩大接触，并为在STEM学科中代表性不足的个人增加科学研究的机会。值得注意的是，缺氧生存的脊椎动物冠军之一的心脏，红耳滑龟（Trachemys scripta）在缺氧期间可以继续有节奏地跳动，尽管速度较慢。先前的研究表明，缺氧海龟表现出的心动过缓是由于其体内固有起搏器急剧而快速的重置。然而，缺氧调节起搏器频率的机制仍不清楚。本研究的主要目的是利用海龟心脏作为模型来阐明心脏起搏器调节的生理和细胞机制。本研究将采用多层次和多学科的方法，系统地研究器官（离体心腔的收缩特性;起搏器动作电位的体外记录）和细胞（离体心肌细胞离子电流的电生理测量）中心脏起搏器的改变，这是缺氧重置固有心率的基础。这项研究将为低氧和低温条件下心脏起搏的分子机制提供重要的见解。两者都与基本的心脏生物学和人类病理学有关，缺氧海龟提供了一个显着的模型，说明这些过程如何在巨大压力的条件下持续存在。