Developing Tools to Understand an Alternative Fate of Urate in Neurodegenerative Diseases

开发工具来了解尿酸盐在神经退行性疾病中的替代命运

• 批准号: 10668103
• 负责人: Norma Frizzell
• 金额: $ 7.45万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10668103
• 关键词: Acceleration; Address; Albumins; Amyotrophic Lateral Sclerosis; Antibodies; Antioxidants; Cellular Stress; Chemicals; Circulation; Clinical; Collection; Corpus striatum structure; Coupled; Detection; Diagnosis; Disease; Disease Progression; Epitopes; Equilibrium; Excision; Exposure to; Future; Generations; Goals; Human; Hydrogen Peroxide; Immunoglobulin G; In Vitro; Infiltration; Inflammation; Inflammatory; Inosine; Investigation; Libraries; Link; Location; Lymphocyte; Lysine; Measurement; Microglia; Movement Disorders; Natural regeneration; Nature; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Oxidative Stress; Parkinson Disease; Patient-Focused Outcomes; Patients; Peptides; Peroxidases; Peroxonitrite; Placebos; Plasma; Population; Post-Translational Protein Processing; Pre-Clinical Model; Predisposition; Process; Prognosis; Prognostic Marker; Proteins; Proteomics; Research Personnel; Rheumatoid Arthritis; Role; Serum; Sodium Chloride; Spinal Cord; Superoxides; Supplementation; Testing; Time; Treatment Efficacy; Urate; Uric Acid; Woman; adduct; cell type; clinical prognosis; disease diagnosis; dopamine transporter; improved; men; motor deficit; neutrophil; novel; oxidation; oxidative damage; polyclonal antibody; prevent; prognostic value; protein function; protein metabolite; protein structure; tool

ABSTRACT Urate is the salt form of uric acid predominantly found in the circulation and is considered a major plasma antioxidant. Low levels of serum urate at diagnosis are associated with accelerated disease progression and lower patient survival in several neurodegenerative diseases. For example, urate levels are lower in Parkinson’s Disease (PD) patients and this correlates with loss of the striatal dopamine transporter and an advanced clinical progression in motor deficits. Similarly, several studies have suggested that urate levels may offer value as a prognostic biomarker for Amyotrophic Lateral Sclerosis (ALS) progression, yet it remains unclear why low uric acid reflects poor survival. Recently, a large effort to increase urate levels (inosine supplementation) in PD patients offered no clinical benefit or improvement in patient outcomes. Why does the supplementation of a major plasma antioxidant confer no benefit to patients in diseases where oxidative stress is known to be present? Our expertise in studying the chemical modification of proteins by metabolites led us to consider an alternative fate of urate when oxidative stress may overwhelm the regeneration of urate antioxidant capacity. We hypothesize that low plasma urate instead reflects increased oxidation of urate to generate reactive urate radicals that can chemically modify protein lysine residues, altering protein structure or function, a process known as protein uratylation. The balance between urate antioxidant benefit, and urate oxidation to damaging radicals, may uniquely depend on the location and nature of the oxidative stress. In this R03 we are embarking on exploratory studies to better understand why urate therapy may not have been as successful as anticipated. Our goal is to generate and validate new tools that will assist movement disorders researchers in the future in testing the relevance of protein uratylation across a range of preclinical models and human biospecimens.

摘要 尿酸盐是尿酸的盐形式，主要存在于循环中，被认为是主要的血浆 抗氧化剂诊断时血清尿酸盐水平低与疾病进展加速相关， 降低了几种神经退行性疾病患者的生存率。例如，帕金森氏症患者的尿酸水平较低， 疾病（PD）患者，这与纹状体多巴胺转运蛋白的丢失和晚期临床 运动缺陷的进展。同样，一些研究表明，尿酸盐水平可能提供价值， 肌萎缩侧索硬化症（ALS）进展的预后生物标志物，但仍不清楚为什么低尿酸 酸反映了生存率低。最近，一个大的努力，以增加尿酸水平（肌苷补充）在PD 患者没有提供临床获益或患者结局的改善。为什么一个专业的补充 血浆抗氧化剂对已知存在氧化应激的疾病患者没有益处？ 我们在研究代谢物对蛋白质的化学修饰方面的专业知识使我们考虑了一种替代方案 当氧化应激可能压倒尿酸盐抗氧化能力的再生时，尿酸盐的命运。我们 假设较低血浆尿酸盐反而反映尿酸盐氧化增加以产生反应性尿酸盐自由基 可以化学修饰蛋白质赖氨酸残基，改变蛋白质结构或功能，这一过程被称为 蛋白尿酰化尿酸盐抗氧化益处和尿酸盐氧化至破坏性自由基之间的平衡， 可能唯一地取决于氧化应激的位置和性质。在R03中，我们正在着手 探索性研究，以更好地了解为什么尿酸盐治疗可能没有预期的成功。我们 我们的目标是开发和验证新的工具，以帮助运动障碍研究人员在未来的测试 蛋白质尿苷酸化在一系列临床前模型和人体生物标本中的相关性。