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.

项目总结/摘要 Peroxiredoxin 6（Prdx6）是一种多功能酶，表达谷胱甘肽过氧化物酶、磷脂酶A2 （PLA2）和溶血磷脂酰胆碱酰基转移酶（LPCAT）活性。Prdx6可以 减少磷脂过氧化氢并水解和再酰化磷脂脂肪酰基键。Prdx6是， 因此，一种完整的酶用于修复过氧化的细胞膜。Prdx6被卷入了 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， 但关于这种独特酶的生物学基本问题仍然没有答案。我们的初步数据显示 这表明Prdx6抑制铁凋亡，这是一种铁依赖性形式的受调节的细胞死亡， 磷脂过氧化氢的积累。新出现的证据表明， 退行性疾病、致癌作用、中风、创伤性脑损伤和缺血/再灌注损伤， 他人因此，建立Prdx6调节铁凋亡的机制和生理相关性， 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活性的作用， Prdx6对胱氨酸摄取抑制、缺氧/复氧和缺氧/复氧诱导的铁凋亡的调节作用 氧中毒我们将使用具有单点突变的小鼠和细胞，这些单点突变会抑制 Prdx 6而不影响其他酶，沿着最先进的分析工具来剖析这种酶的作用 对铁下垂的调节作用。在第二个项目中，我建议研究Prdx6在维护 线粒体功能我们的初步数据表明，Prdx6缺陷改变了 线粒体代谢和减少线粒体呼吸。我们将研究催化剂的作用 Prdx6对线粒体形态、动力学和功能的活性，使用细胞外通量测定， 三维成像技术。这项建议的结果将有助于我们了解一个 细胞氧化还原平衡的关键介质。这些结果也将为未来的研究提供必要的信息。 用于预防和治疗与氧化还原失调相关的疾病的转化策略 体内平衡