Molecular MR Imaging of Hepatic Fibrogenesis

项目摘要 非酒精性脂肪性肝病(NAFLD)是导致肝脏疾病的最主要原因，20%-30%的成年人 西方世界现在估计有非酒精性脂肪肝。在非酒精性脂肪肝中，肝细胞积累过多的脂肪(脂肪变性)， 这是良性的和可逆的。然而，高达30%的NAFLD患者将发展为非酒精性 脂肪性肝炎(NASH)，以脂肪变性、炎症和瘢痕形成(纤维化)为特征。患有疾病的患者 只有脂肪变性才有良好的长期预后，与肝脏相关的发病率或死亡率没有增加，但 伴有NASH的患者会增加患肝硬变、肝细胞癌和死亡率的风险。纳什预计很快会 是肝移植的主要适应症。NAFLD/NASH的财政负担目前估计为 仅在美国就花费了1000亿美元。迫切需要确定有患非酒精性脂肪肝的风险的患者。 发展NASH和肝硬变，以通过改善生活方式、锻炼来更好地管理患者的医疗保健 和节食。此外，大量新疗法已进入临床试验，有效的诊断方法是 需要更好地将患者分层纳入这些试验，并准确监测对治疗的反应。 纤维化期，而不是脂肪变性或炎症，是疾病的唯一特征，与病情恶化有关 纳什的结果。除了活检之外，我们还缺乏良好的工具来无创地检测肝纤维化、分期纤维化或 监测对治疗的反应。弹性成像方法对疾病的早期变化不敏感。血清 用于识别NASH和/或肝纤维化的生物标记物和生物标记物面板也是有限的，并且缺乏准确性 准备好了。这些技术都没有监测治疗的准确性。一种准确、安全的诊断方法 监测NASH及其相关的纤维化在临床实践和临床研究中都具有极其重要的意义。 我们最近在动物模型中证明，我们可以非侵入性地量化纤维形成(活动性疾病)。 使用分子磁共振(MR)探针Gd-hyd，目标是细胞外烯丙氨酸，一种化学物质 氧化胶原蛋白的修饰，仅在活动性纤维化形成过程中出现。我们证明了Gd-HYD成像可以 检测纤维化形成，监测治疗反应，并可区分活动期纤维化和稳定期瘢痕 肺、肝纤维化模型。这个项目的总体目标是改进这个原型，以开发一个 优化的肝纤维化磁共振探头，用于对患者的肝纤维化进行稳健、定量的研究。

Project Summary Nonalcoholic fatty liver disease (NAFLD) is the most prominent cause of liver disease, with 20-30% of adults in the western world now estimated to have NAFLD. In NAFLD, hepatocytes accumulate excess fat (steatosis), which is benign and reversible. However up to 30% of patients with NAFLD will develop non-alcoholic steatohepatitis (NASH) which is characterized by steatosis, inflammation, and scarring (fibrosis). Patients with only steatosis have good long-term prognosis, with no increased liver related morbidity or mortality, but those with NASH have increased risk of cirrhosis, hepatocellular carcinoma and mortality. NASH is expected to soon be the leading indication of liver transplantation. The financial burden of NAFLD/NASH is currently estimated to cost >$100 billion in the USA alone. There is an urgent need to identify NAFLD patients who are at risk of developing NASH and cirrhosis so as to better manage patient healthcare through improved lifestyle, exercise and diet. In addition, a large number of new therapies have entered clinical trials and effective diagnostics are needed to better stratify patients into these trials and to accurately monitor response to therapy. Fibrosis stage, and not steatosis nor inflammation, is the only feature of disease associated with worse outcomes in NASH. Besides biopsy we lack good tools to noninvasively detect liver fibrosis, stage fibrosis, or monitor response to treatment. Elastography methods are not sensitive to early changes in disease. Serum biomarkers and biomarker panels to identify NASH and/or liver fibrosis, are also limited and lack accuracy for staging. None of these techniques has the accuracy to monitor treatment. An accurate, safe method to diagnose and monitor NASH and associated fibrosis is of utmost importance in both clinical practice and clinical research. We recently demonstrated in animal models that we could quantify fibrogenesis (active disease) noninvasively using a molecular magnetic resonance (MR) probe, Gd-Hyd, that targets extracellular allysine, a chemical modification of oxidized collagen, present only during active fibrogenesis. We showed that Gd-Hyd imaging could detect fibrogenesis, monitor treatment response and could distinguish active fibrogenesis from stable scar in models of lung and liver fibrosis. The overall goal of this project is to improve on this prototype to develop an optimized fibrogenesis MR probe for robust, quantification of liver fibrogenesis in patients.