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

NSF/BIO-DFG：细胞色素 c 氧化酶对全身血管细胞缺氧的适应 - 从结构到功能

• 批准号: 2329629
• 负责人: Lawrence Grossman
• 金额: $ 122.52万
• 依托单位: Wayne State University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2329629&HistoricalAwards=false
• 关键词: NSF; BIO; DFG; Cytochrome; oxidase

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.

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。该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，以便能够在压力下更有效地发挥作用。这将通过确定亚基在短暂或持续低氧水平后如何变化，以及这些变化对能量使用功能和细胞部分（例如线粒体）功能的影响来完成。最后，这些结果将与其他类型的应力（例如热或温度变化）引起的结果进行比较。该项目还将为高中、本科生和研究生水平的未来科学家提供绝佳的机会。 PI 将特别鼓励来自底特律地区资金不足社区、以前从未参与过研究的本科生研究人员。了解如何感知氧气水平的知识为未来的医学研究提供了潜力，可以为因压力、污染或疾病引起的低氧气水平而导致细胞受损的疾病和病症提供治疗方法，从而促进社会中个人的福祉。氧气水平的变化对需氧生物构成重大威胁，因此它们投入大量资源来抵消和尽量减少随之而来的损害。最近发现的一种机制是细胞色素 c 氧化酶（COX 或复合体 IV）的重新配置，它是线粒体电子传递链 (ETC) 氧的最终调节电子供体。低氧水平会导致 14 个 COX 亚基中某些亚基的表达发生变化，尽管这一过程仍有很多未知之处。该项目将研究缺氧诱导的 COX 重塑的原因和后果，重点关注先前确定的原代细胞中关键的氧依赖性 COX 亚基，并将建立这些亚基与氧化还原传感和信号传导的联系。该项目将涉及：（1）表征系统周细胞中COX亚基亚型组成对慢性缺氧的动态调节，并与系统血管细胞进行比较； (2) 慢性缺氧时 COX 重塑的结构后果的表征； (3) COX 重塑对线粒体和细胞健康的功能影响的表征； (4) COX 重塑的主要发现与对其他应激刺激的反应的比较。因此，该项目将揭示并确定 COX 亚基表达介导的线粒体氧和氧化还原信号传导的基本调节机制。该美国/德国合作项目得到美国国家科学基金会和德国研究基金会 (Deutsche Forschungemeinschaft) 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价值和更广泛的影响审查标准进行评估，被认为值得支持。