Project 1: AMPK and Inflammation in Gout

项目摘要 在痛风中，急性关节炎发作通常是严重的，并损害生活质量。急性痛风发作早期增加， 持续数年，在滴定和维持最初几年的其他成功的降尿酸治疗中 （二）。然而，症状性痛风表现为痛风发作。此外，痛风并不均匀 在无症状的高尿酸血症中发展，尽管约25%可检测到组织尿酸盐结晶沉积。血清尿酸盐 (sUA)水平有助于指导临床决策，例如，针对特定sUA目标的治疗，或确定治疗有效性 （监测生物标志物）。sUA符合痛风替代生物标志物的标准，作为临床研究的替代终点 审判然而，sUA在评估痛风的炎症状态方面没有明确的作用。因此，有重大 对更好的生物标志物的未满足需求，不仅用于无症状高尿酸血症中的痛风事件，而且用于 痛风患者将发展更频繁和严重的耀斑，从而推进痛风精准医学 (CORT通过预测需求和持续时间，并监测潜在毒性痛风发作的有效性 秋水仙碱或NSAID预防，特别是在开始和维持ULT后。我们的科学前提直接 解决了这些需求，建立在我们最近的发现，代谢能量生物传感器AMP激活 激酶（AMPK）控制模型痛风炎症的“开关”。值得注意的是，AMPK也是一个 秋水仙碱和甲氨蝶呤治疗效果的主要转换器。此外，我们提出了惊人的 与健康对照相比，痛风患者PBL AMPK活性减弱的初步研究。在这里，我们将 翻译基本的发现，组成型AMPK活性显着限制尿酸盐的炎症潜力 部分通过抑制炎症主要调节因子NF-κB的激活，以及限制尿酸盐的摄入， 晶体NLRP 3炎性体活化/巨噬细胞释放IL-1β。重要的是，AMPK活性 调节和反映营养，碳水化合物代谢和炎症应激，与组织AMPK 已知在肥胖症、代谢综合征和2型糖尿病中活性降低。重要的是，低AMPK 活动促进常见痛风合并症（CORT主题），即高血压、CKD发作、进展 以及相关的肾纤维化、心脏肥大和非酒精性脂肪肝。为了检验这一假设 AMPK活性降低预示着更频繁和更严重的炎症性痛风性关节炎发作，我们将检测PBL AMPK活性和特定AMPK靶向代谢物（通过代谢组学评估）在痛风，健康对照， 和无症状的高尿酸血症。我们将在VA CSP 594中对痛风受试者进行辅助研究 滴定别嘌呤醇与非布司他单药的有效性比较研究，滴定至尿酸盐目标，但伴有发作 第72周作为主要终点。我们还将检验这一假设，即在痛风中，PBL AMPK活性低是一个重要的因素。 炎症发作/年中位数以上患者和NF-κB活性增加的标志物。 项目完成将把炎症的代谢调节转化为一种新型生物标志物和目标， 预防急性痛风发作。

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.