Project 1: AMPK and Inflammation in Gout

项目 1：AMPK 与痛风炎症

• 批准号: 10263204
• 负责人: Robert A. Terkeltaub
• 金额: $ 28.29万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-20 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10263204
• 关键词: 5' -AMP-activated protein kinase; Acute; Address; Age; Allopurinol; Ancillary Study; Anti-Inflammatory Agents; Arthritis; Attenuated; Basic Science; Biological Assay; Biological Markers; Biosensor; Cardiovascular system; Caring; Clinical Trials; Colchicine; Crystallization; Deposition; Diabetes Mellitus; Effectiveness; Enzyme-Linked Immunosorbent Assay; Flare; Frequencies; Gender; Gilbert Disease; Gout; Gouty Arthritis; Health; Heart Hypertrophy; Homeostasis; Hospitalization; Hypertension; Hyperuricemia; Impairment; In Vitro; Inflammasome; Inflammation; Inflammatory; Interleukin-1 beta; Investigation; Kidney; Lead; Leukocytes; Link; Maintenance; Maintenance Therapy; Metabolic; Metabolic syndrome; Methotrexate; Modeling; Monitor; Non-Insulin-Dependent Diabetes Mellitus; Non-Steroidal Anti-Inflammatory Agents; Obesity; Outcome; Patients; Periodicity; Phase; Predisposition; Prophylactic treatment; Prospective Studies; Quality of life; Reference Standards; Regulation; Risk; Role; Sampling; Serum; Severities; Site; Surrogate Endpoint; Surrogate Markers; Testing; Therapeutic Effect; Therapy trial; Tissues; Titrations; Transducers; Translating; Translational Research; Treatment Efficacy; Urate; Uric Acid; Work; activity marker; aged; arthropathies; autoinflammatory; carbohydrate metabolism; chemokine; clinical decision-making; comorbidity; comparative effectiveness study; cost effective; febuxostat; in vivo; innovation; kidney fibrosis; macrophage; metabolomics; multidisciplinary; non-alcoholic; nonalcoholic steatohepatitis; novel marker; nutrition; p65; patient oriented; peripheral blood; precision medicine; predictive marker; prevent; primary endpoint; prospective; response; stressor; targeted treatment; transcription factor

PROJECT SUMMARY In gout, acute arthritis flares are often severe, and impair quality of life. Acute gout flares increase early, and persist for years, in the titration and first years of maintenance of otherwise successful urate-lowering therapy (ULT). Yet symptomatic gout manifests variably in established gout. Furthermore, gout does not uniformly develop in asymptomatic hyperuricemia, despite detectable tissue urate crystal deposits in ~25%. Serum urate (sUA) level helps guide clinical decision-making, eg, ULT to specific sUA target, or to identify ULT efficacy (monitoring biomarker). sUA fulfills criteria for gout surrogate biomarker, as a surrogate end point in clinical trials. However, sUA has no clear role in assessing the inflammatory state in gout. As such, there is major unmet need for better biomarkers not only for incident gout in asymptomatic hyperuricemia, but also for which gout patients will develop more frequent and severe flares, and thereby, to advance gout precision medicine (CORT theme), by predicting need and duration, and monitor effectiveness of potentially toxic gout flare colchicine or NSAID prophylaxis, particularly after starting and maintaining ULT. Our scientific premise directly addresses these needs, building on our recent discovery that the metabolic energy biosensor AMP activated Kinase (AMPK) controls "on and off switches" for model gouty inflammation. Remarkably, AMPK also is a primary transducer of therapeutic effects of colchicine and methotrexate. Moreover, we present striking Preliminary Studies for attenuated PBL AMPK activity in gout compared to healthy controls. Here, we will translate basic findings that constitutive AMPK activity markedly limits the inflammatory potential of urate crystals in vivo, partly by blunting activation of the inflammation master regulator NF-κB, and by limiting urate crystal NLRP3 inflammasome activation/IL-1β release by macrophages. Significantly, AMPK activity both regulates and reflects nutrition, carbohydrate metabolism, and inflammatory stressors, with tissue AMPK activity known to be diminished in obesity, metabolic syndrome, and type 2 diabetes. Significantly, low AMPK activity promotes common gout comorbid conditions (CORT theme), ie, hypertension, CKD onset, progression and associated renal fibrosis, cardiac hypertrophy, and nonalcoholic steatohepatosis. To test the hypothesis that low AMPK activity predicts more frequent and severe inflammatory gouty arthritis flares, we will assay PBL AMPK activity, and specific AMPK-targeted metabolites (assessed by metabolomics) in gout, healthy controls, and asymptomatic hyperuricemia. We will perform an ancillary study of gout subjects in the VA CSP594 comparative effectiveness study of titrated allopurinol vs. febuxostat ULT, titrated to urate target, but with flares at 72 weeks as the primary endpoint. We also will test the hypothesis that, in gout, low PBL AMPK activity is a marker for patients with greater than the median inflammatory flares/year, and for increased NF-κB activity. Project completion will translate metabolic regulation of inflammation to a novel biomarker and target for preventing acute gout flares.

项目总结