NSF/BIO-DFG: Cytochrome c oxidase adaptation to hypoxia in systemic vascular cells - From structure to function

呼吸氧气的生物的所有细胞都必须对氧气水平的变化做出反应。这个项目将研究低氧水平引起的压力如何导致关键酶COX改变其蛋白质组成，以便能够在这种压力下更有效地发挥作用。这将通过确定在短时间或持续低水平氧气后亚基如何变化，以及这些变化对能量使用功能和细胞部分(如线粒体)功能的影响来完成。最后，将这些结果与其他类型的压力，如热或温度变化引起的结果进行比较。这个项目还将提供极好的机会，让未来的科学家在高中、本科生和研究生层面上参与进来。PI将特别鼓励来自底特律地区资金不足社区的本科生研究人员，他们以前没有参与过研究。了解氧气水平是如何被感知的，有可能为未来的医学研究提供治疗，治疗因压力、污染或疾病引起的低氧气水平而导致的疾病和细胞受损的情况，从而促进社会上个人的福祉。氧气水平的变化对有氧生物体构成主要威胁，因此它们投入了相当大的资源来抵消和减少由此造成的损害。最近发现的一种机制是细胞色素C氧化酶(COX或复合体IV)的重组，它是线粒体电子传输链(ETC)中最终的、调节氧的电子供体。低氧水平导致14个COX亚基中的一些亚基的表达发生变化，尽管对这一过程仍有许多未知之处。该项目将研究低氧诱导的COX重塑的原因和后果，重点关注先前发现的原代细胞中关键的氧依赖COX亚基，并将这些亚基与氧化还原感知和信号转导联系起来。该项目将涉及：(1)系统周细胞对慢性低氧反应的COX亚基亚基组成的动态调节，以及与系统血管细胞的比较；(2)COX重塑对慢性低氧的结构影响的特征；(3)COX重塑对线粒体和细胞健康的功能影响的特征；(4)COX重塑对其他应激刺激反应的关键结果的比较。因此，该项目将揭示和识别由COX亚单位表达介导的线粒体氧和氧化还原信号的基本调控机制。这一美国/德国合作项目得到了美国国家科学基金会和德国研究基金会(Deutsche Forschungeminschaft)的支持。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。

All cells in oxygen-breathing creatures must react to changes in oxygen levels. This project will examine how stress caused by low oxygen levels causes a key enzyme, COX, to change its protein composition to be able to function more efficiently under that stress. This will be done by determining how the subunits change after short or continuously low levels of oxygen, and the consequences of these changes on the function of energy usage and function of parts of the cell such as mitochondria. Finally, these results will be compared to those caused by other kinds of stress such as heat or changes of temperature. This project will also offer excellent opportunities to engage future scientists at the high school, undergraduate, and graduate student levels. The PIs will especially encourage undergraduate researchers from underfunded communities in the Detroit area who have not participated in research before. Knowledge of how oxygen levels are sensed holds potential for future medical research to provide treatments for diseases and conditions in which cells are compromised due to low oxygen levels caused by stress, pollution, or disease, thereby promoting the well-being of individuals in society.Changes in oxygen levels pose major threats to aerobic organisms, and they accordingly devote considerable resources to counteracting and minimizing the consequent damage. One such recently uncovered mechanism is the reconfiguration of cytochrome c oxidase (COX or complex IV), the final and regulatory electron donor to oxygen of the mitochondrial electron transport chain (ETC). Low oxygen levels induce changing expression of some of the 14 COX subunits, although much remains unknown about this process. This project will investigate the cause and consequences of hypoxia-induced COX remodeling with a focus on previously identified key oxygen-dependent COX subunits in primary cells, and will establish a link of these subunits to redox sensing and signaling. The project will involve: (1) characterization of the dynamic regulation of COX subunit isoform composition in systemic pericytes in response to chronic hypoxia, and comparison to that of systemic vascular cells; (2) characterization of structural consequences of COX remodeling upon chronic hypoxia; (3) characterization of functional consequences of COX remodeling on mitochondrial and cellular health; and (4) comparison of key findings of COX remodeling to responses to other stress stimuli. The project will thus uncover and identify fundamental regulatory mechanisms of mitochondrial oxygen and redox signaling mediated by COX subunit expression.This collaborative US/Germany project is supported by the US National Science Foundation and the German Research Foundation (Deutsche Forschungemeinschaft).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.