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一种关键酶考克斯改变其蛋白质组成，以便在这种压力下更有效地发挥作用。这将通过确定亚基在短时间或持续低水平的氧气后如何变化以及这些变化对能量使用功能和细胞部分功能（如线粒体）的影响来完成。最后，这些结果将与其他类型的应力（如热量或温度变化）引起的结果进行比较。该项目还将提供极好的机会，让未来的科学家在高中，本科和研究生水平。PI将特别鼓励来自底特律地区资金不足社区的本科研究人员，他们以前没有参加过研究。氧气水平如何被感知的知识为未来的医学研究提供了潜在的可能性，以治疗由于压力、污染或疾病引起的低氧水平而损害细胞的疾病和状况，从而促进社会中个人的福祉。氧气水平的变化对好氧生物构成了重大威胁，因此他们投入大量资源来抵消和减少随之而来的损害。最近发现的一个这样的机制是细胞色素c氧化酶（考克斯或复合物IV）的重构，线粒体电子传递链（ETC）的氧的最终和调节电子供体。低氧水平诱导14个考克斯亚基中的一些亚基的表达改变，尽管关于该过程仍有许多未知。本项目将研究缺氧诱导的考克斯重塑的原因和后果，重点是以前确定的主要氧依赖性考克斯亚基在原代细胞中，并将建立这些亚基的氧化还原传感和信号的联系。该项目将涉及：（1）表征响应于慢性缺氧的系统性周细胞中考克斯亚基同种型组成的动态调节，并与系统性血管细胞的动态调节进行比较;（2）表征慢性缺氧时考克斯重构的结构后果;（3）表征考克斯重构对线粒体和细胞健康的功能后果;（4）比较考克斯重塑与其他应激刺激反应的关键发现。因此，该项目将揭示和确定由考克斯亚基表达介导的线粒体氧和氧化还原信号的基本调控机制。（Deutsche Forschungemeinschaft）该奖项反映了NSF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进行评估，被认为值得支持审查标准。

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.