The Biology of Peroxiredoxin 6

过氧化还原蛋白 6 的生物学

• 批准号: 10686366
• 负责人: Jose P Vazquez Medina
• 金额: $ 37.68万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10686366
• 关键词: Acute Lung Injury; Acylation; Acyltransferase; Affect; Antioxidants; Applications Grants; Biochemical Pathway; Biological Assay; Biology; Catalytic Domain; Cell Death; Cell Respiration; Cell membrane; Cells; Central Nervous System Diseases; Chronic; Cystine; Data; Degenerative Disorder; Disease; Enzymes; Equilibrium; Future; Gene Expression Profile; Homeostasis; Hydrogen Peroxide; Hypoxia; Imaging Techniques; Inflammation; Iron; Ischemia; Lysophosphatidylcholines; Maintenance; Male Infertility; Mediator; Mitochondria; Morphology; Mus; Muscular Atrophy; Non-Insulin-Dependent Diabetes Mellitus; Oxidation-Reduction; Pathway interactions; Phospholipase A2; Phospholipids; Physiological; Point Mutation; Prevention strategy; Proteins; Regulation; Reperfusion Injury; Respiration; Retinal Diseases; Role; Stroke; Three-Dimensional Imaging; Traumatic Brain Injury; analytical tool; carcinogenesis; cell growth regulation; extracellular; glutathione peroxidase; interest; mitochondrial metabolism; novel; oxygen toxicity; peroxiredoxin; repair enzyme; translational approach; uptake

Project Summary/Abstract Peroxiredoxin 6 (Prdx6) is a multi-functional enzyme that expresses glutathione peroxidase, phospholipase A2 (PLA2), and lysophosphatidylcholine acyltransferase (LPCAT) activities in separate catalytic sites. Prdx6 can reduce phospholipid hydroperoxides and hydrolyze and re-acylate phospholipid fatty acyl bonds. Prdx6 is, therefore, a complete enzyme for the repair of peroxidized cell membranes. Prdx6 has been implicated in several pathophysiological conditions, including acute lung injury, inflammation, carcinogenesis, various chronic central nervous system diseases, retinal disease, type 2 diabetes, muscle atrophy, and male infertility, but basic questions about the biology of this unique enzyme remain unanswered. Our preliminary data strongly suggest that Prdx6 suppresses ferroptosis, an iron-dependent form of regulated cell death driven by the accumulation of phospholipid hydroperoxides. Emerging evidence implicates ferroptosis in several degenerative diseases, carcinogenesis, stroke, traumatic brain injury, and ischemia/reperfusion injury, among others. Hence, establishing the mechanisms and physiological relevance of ferroptosis regulation by Prdx6 is crucial. My lab is interested in studying the role of the glutathione peroxidase, PLA2, and LPCAT activities of Prdx6 on the regulation of ferroptosis induced by inhibition of cystine uptake, hypoxia/reoxygenation, and oxygen toxicity. We will use mice and cells with single point mutations that inactivate each of the activities of Prdx6 without affecting the others, along with state-of-the-art analytical tools to dissect the role of this enzyme on the regulation of ferroptosis. In a second project, I propose to study the role of Prdx6 in the maintenance of mitochondrial function. Our preliminary data show that Prdx6 deficiency alters transcriptional signatures of mitochondrial metabolism and reduces mitochondrial respiration. We will study the effects of the catalytic activities of Prdx6 on mitochondrial morphology, dynamics, and function using extracellular flux assays and three-dimensional imaging techniques. The results of this proposal will contribute to our understanding of one of the critical mediators of cellular redox balance. These results will also provide essential information for future translational strategies for the prevention and treatment of diseases associated with dysregulated redox homeostasis.

项目摘要/摘要 过氧蛋白6（PRDX6）是一种表达谷胱甘肽过氧化物酶A2的多功能酶 （PLA2）和在单独的催化位点中的溶血磷脂酰胆碱转移酶（LPCAT）活性。 prdx6可以 减少磷脂氢过氧化物，并水解并重新酰化磷脂脂肪酰基键。 prdx6是， 因此，一种用于修复过氧化细胞膜的完整酶。 PRDX6与 几种病理生理状况，包括急性肺损伤，炎症，癌变，各种 慢性中枢神经系统疾病，视网膜疾病，2型糖尿病，肌肉萎缩和男性不育症， 但是关于这种独特酶的生物学的基本问题仍未得到解答。我们的初步数据强烈 表明PRDX6抑制了铁铁作用，这是一种由铁依赖的受调节细胞死亡形式 磷脂氢过氧化物的积累。新兴的证据暗示了一些 退化性疾病，癌变，中风，脑外伤和缺血/再灌注损伤 其他的。因此，建立PRDX6的铁凋亡调节的机制和生理相关性是 至关重要的。我的实验室有兴趣研究谷胱甘肽过氧化物酶，PLA2和LPCAT活动的作用 PRDX6关于抑制胱氨酸摄取，缺氧/重氧和抑制肌t的调节的pRDX6 氧毒性。我们将使用带有单点突变的小鼠和细胞，使每种活动的活性失活 PRDX6不影响其他人，以及最先进的分析工具来剖析该酶的作用 关于铁铁作用的调节。在第二个项目中，我建议研究PRDX6在维持中的作用 线粒体功能。我们的初步数据表明，PRDX6缺乏症改变了转录特征 线粒体代谢并降低线粒体呼吸。我们将研究催化的影响 PRDX6的活动对线粒体形态，动力学和功能，使用细胞外通量测定和功能 三维成像技术。该提案的结果将有助于我们理解一个 细胞氧化还原平衡的关键介体。这些结果还将为未来提供基本信息 预防和治疗与氧化还原失调相关的疾病的翻译策略 稳态。

项目成果

Editorial: Reactive oxygen species (ROS) signaling during cytoskeleton dynamics.

• DOI: 10.3389/fcell.2023.1295263
• 发表时间: 2023
• 期刊: FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
• 影响因子: 5.5
• 作者: Nakao, Lia S.;Olson, Michael F.;Vazquez-Medina, Jose Pablo;Valdivia, Alejandra
• 通讯作者: Valdivia, Alejandra