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.

氧气中的所有细胞都必须对氧气水平的变化做出反应。该项目将检查低氧水平引起的压力如何导致关键酶Cox改变其蛋白质成分，以便在这种应力下能够更有效地发挥作用。这将通过确定在短或连续低水平的氧气后确定亚基如何变化，以及这些变化对细胞部分（例如线粒体）部分的能量使用和功能的影响。最后，将将这些结果与由热量或温度变化等其他压力引起的结果进行比较。该项目还将为吸引高中，本科生和研究生级别的未来科学家提供绝佳的机会。 PI会特别鼓励来自底特律地区资金不足社区的本科研究人员以前从未参加过研究。了解氧气水平的知识具有未来的医学研究的潜力，可以为疾病和疾病提供治疗，其中细胞由于压力，污染或疾病引起的低氧水平而受到损害的疾病，从而促进了社会中个体的幸福感，从而改变了氧气水平的变化，造成了对有氧有机体的主要威胁，并损害了有效的资源，并造成了不利的造成的，并造成了不利的影响。最近未发现的机制是细胞色素C氧化酶（COX或复合物IV）的重新配置，即对线粒体电子传输链（ETC）氧的最终和调节电子供体。低氧水平诱导14个Cox亚基中一些表达的变化，尽管对此过程尚不清楚。该项目将研究缺氧诱导的COX重塑的原因和后果，重点是原代细胞中先前确定的关键氧依赖性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）表征全身性周细胞中Cox亚亚基同工型组成的动态调节，以响应慢性缺氧，以及与全身血管细胞的动态调节； （2）表征Cox重塑慢性缺氧的结构后果； （3）表征Cox重塑线粒体和细胞健康的功能后果； （4）比较Cox重塑对其他应力刺激的反应的关键发现。因此，该项目将发现并确定由Cox亚基表达介绍的线粒体氧和氧化还原信号传导的基本调节机制。该协作美国/德国项目得到了美国国家科学基金会和德国研究基金会（Deutsche Forschemcheminschaft）的支持，该项目通过Infortial the Infornation Indernitory deedy teed deemectial reptig nsfortiqu the Infortial the Infortial the Inderitial deedy award awection。更广泛的影响审查标准。