Glutathionylated Products of Radical-Induced Lipid Oxidation in Inflammatory Disease

炎症性疾病中自由基诱导的脂质氧化的谷胱甘肽化产物

• 批准号: 10736332
• 负责人: Robert Gerd Salomon
• 金额: $ 39.45万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10736332
• 关键词: Abbreviations; Acids; Address; Age related macular degeneration; Agonist; Anabolism; Autophagocytosis; Biological; Cells; Choroid; Complex; Cytokine Signaling; Detection; Development; Disease; Disease Marker; Docosahexaenoic Acids; Esters; Ethanolamines; Exhibits; Eye diseases; Free Radicals; Functional disorder; Gene Expression; Generations; Glutathione; Human; Immunoassay; In Vitro; Inflammation; Inflammatory; Interleukin-13; Knowledge; Lactones; Lecithin; Leukotriene A4; Leukotriene C4; Leukotriene D4; Leukotriene E4; Leukotriene Receptor; Leukotrienes; Light; Link; Lipids; Measures; Metabolism; Mitochondria; Modeling; Molecular; NADH; Ocular Pathology; Oxidative Stress; Oxygen; Pathogenesis; Pathologic; Pathologic Neovascularization; Pathology; Phospholipase A2; Phospholipids; Physiological; Physiology; Pilot Projects; Post-Translational Protein Processing; Production; Pyrroles; Rattus; Research; Retina; Retinal Degeneration; Retinal Edemas; Role; Scheme; Signal Pathway; Structure; Structure of retinal pigment epithelium; Testing; Therapeutic; Therapeutic Intervention; Time; Zileuton; analog; arachidonate; clinical development; cross reactivity; cysteinyl leukotriene receptor; cysteinyl-leukotriene; disabling disease; in vivo; insight; novel therapeutics; oxidation; polyunsaturated fat; protein expression; receptor; response; retinal damage; therapeutic development; transcriptome sequencing

Limited knowledge of the structures and biological activities of products generated by free radical-induced lipid oxidation in the retina is a barrier to progress in the development of clinically useful new disease markers and mechanistically informed therapeutic interventions. Understand- ing cellular responses to free radical-induced lipid oxidation products is complex owing to their diversity and ability to mimic enzymatically generated receptor agonists. Their unrecognized generation and biological activities almost certainly contribute to the mediocre efficacy of currently available therapeutic measures for age related macular degeneration (AMD). We discovered glutathione (GSH) derivatives produced from oxidatively truncated arachidonyl phospholipids that are structural and functional analogues of cysteinyl (Cys) leukotrienes (LTs). We refer to them as pseudo (ø)LTs. We will test the hypotheses that øLTs contribute to retinal pathology and physiology in a rat model of light-induced retinal degeneration. Pilot studies show that øLTs are present in human retina, are produced in vivo consequent to oxidative insult, and exhibit LT-like biological activities. Therefore, øLTs can elicit cellular responses erroneously presumed to be induced exclusively by CysLTs. Consequently, they are a confounding factor for interpreting previous studies on the involvements of LTs in retinal pathology and physiology. The proposed research will test the hypotheses that øLTs and related GSH derivatives of oxidatively truncated docosahexaenoyl phospholipids contribute to receptor-dependent inflammatory cytokine signal- ing, retinal edema, pathological neovascularization, or physiologically important initiation of retinal pigment epithelium (RPE) autophagy. The potential pathophysiological significance of these glutathionylated products of lipid oxidation lies in the possibility of their ubiquitous generation in high levels, e.g., compared to those of CysLTs. We will test the conclusion of preliminary studies that øLTs are LT receptor agonists and determine if their ability to induce the expression of IL-13 and TGF-b1 promotes LT biosynthesis. Because cross reactivity may confound the interpretation of immunoassays, we quantitate øLTs and LTs by LC-MS/MS. We will determine signaling path- ways, e.g., with RNA-Seq studies, activated by glutathionylated products of free radical-induced lipid oxidation addressing the questions: do they promote inflammation in ocular pathology or initiate autophagy in RPE cells and how do they do it? Molecular level insights into the role of oxidative stress in the pathogenesis of inflammatory eye diseases such as AMD can facilitate development of therapeutic interventions that ameliorate the progression of these common but disabling diseases.

自由产生的产品结构和生物活动的了解有限 视网膜中自由基诱导的脂质氧化是临床发展发展的障碍 有用的新疾病标记和机械知情的治疗干预措施。理解- 细胞对自由基诱导的脂质氧化产物的反应是复杂的 多样性和模仿酶产生的接收器的能力。他们无法认可 几乎可以肯定的发电和生物活动有助于当前的媒体效率 与年龄相关的黄斑变性（AMD）的可用治疗指标。我们发现了 谷胱甘肽（GSH）衍生物是由氧化截短的蛛网膜磷脂产生的 是白细胞（Cys）白细胞（LTS）的结构和功能类似物。我们称他们为 伪（Ø）LTS。我们将检验Ølts有助于视网膜病理和 在光引起的视网膜变性的大鼠模型中的生理学。试点研究表明Ølts是 存在于人视网膜中，是由氧化侮辱引起的体内产生的，并表现出LT样 生物活动。因此，Ølts可以错误地认为是错误的细胞反应 仅由CYSLT诱导。因此，它们是解释的混杂因素 先前关于LTS参与视网膜病理学和生理学的研究。提议 研究将检验Ølts和相关的GSH衍生物的假设 Docosahexaenoyl磷脂有助于接收器依赖性炎症细胞因子信号 - ING，视网膜水肿，病理新生血管形成或视网膜物理上重要的倡议 色素上皮（RPE）自噬。这些的潜在病理生理意义 脂质氧化的谷胱甘肽化产物在于它们在其无处不在的可能性中 与CYSLT相比，高水平。我们将测试初步研究的结论 Ølts是LT受体激动剂，并确定它们是否诱导IL-13的表达能力 TGF-B1促进了LT生物合成。因为交叉反应可能会混淆解释 我们将确定信号通道路径 - 例如，通过RNA-seq研究，通过自由基诱导的谷胱甘肽产物激活 脂质氧化解决问题：它们是否促进眼病理中的炎症 或在RPE细胞中启动自噬，它们如何做？分子水平对角色的见解 诸如AMD之类的炎性眼病的发病机理中氧化应激的发病机理可以促进 发展理论干预措施，可以改善这些常见的发展，但 禁用疾病。