Molecular MR Imaging of Hepatic Fibrogenesis

肝纤维化的分子磁共振成像

• 批准号: 10360979
• 负责人: Peter D Caravan
• 金额: $ 13.11万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-03 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10360979
• 关键词: Adult; Alcoholic Liver Cirrhosis; Animal Model; Atrial Fibrillation; Benign; Biopsy; Chemicals; Chronic Disease; Chronic Hepatitis; Cicatrix; Cirrhosis; Clinical Research; Clinical Trials; Collagen; Diabetic Nephropathy; Diagnosis; Diagnostic; Disease; Disease Progression; Fatty acid glycerol esters; Fibrosis; Financial Hardship; Goals; Healthcare; Hepatic Fibrogenesis; Hepatocyte; Human; Hypertrophic Cardiomyopathy; Image; Inflammation; Life Style; Liver; Liver Fibrosis; Liver diseases; Magnetic Resonance; Magnetic Resonance Imaging; Methods; Modeling; Modification; Molecular; Monitor; Morbidity - disease rate; Outcome; Oxides; Patients; Pharmacotherapy; Primary carcinoma of the liver cells; Prognosis; Pulmonary Fibrosis; Risk; Serum; Staging; Techniques; Tissues; Western World; biomarker panel; clinical practice; cost; diet and exercise; elastography; extracellular; fibrogenesis; imaging probe; improved; liver transplantation; mortality; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel therapeutics; patient stratification; prototype; response; tool; treatment response

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.

项目摘要 非酒精性脂肪肝病（NAFLD）是肝病最突出的原因，成年人中有20-30％ 现在，西方世界估计有NAFLD。在NAFLD中，肝细胞会积聚多余的脂肪（脂肪变性）， 这是良性和可逆的。但是，多达30％的NAFLD患者会出现非酒精性 脂肪性肝炎（NASH）的特征是脂肪变性，炎症和疤痕（纤维化）。患者 只有脂肪变性具有良好的长期预后，没有相关的发病率或死亡率增加，但是 纳什的肝硬化，肝细胞癌和死亡率的风险增加。纳什有望很快 成为肝移植的主要指示。 NAFLD/NASH的财务负担目前估计为 仅在美国，成本> 1000亿美元。迫切需要识别有风险的NAFLD患者 发展纳什和肝硬化，以通过改善生活方式更好地管理患者医疗保健 和饮食。此外，许多新疗法已进入临床试验，有效的诊断是 需要更好地将患者分类为这些试验并准确监测对治疗的反应。 纤维化阶段，而不是脂肪变性，也不是炎症，是疾病的唯一特征 纳什的结果。除活检以外，我们缺乏非侵入性检测肝纤维化，期纤维化或 监测对治疗的反应。弹性方法对疾病的早期变化不敏感。血清 生物标志物和生物标志物面板以识别纳什和/或肝纤维化，也有限，并且缺乏准确性 舞台。这些技术都没有监测治疗的准确性。准确，安全的诊断方法 在临床实践和临床研究中，监测NASH和相关的纤维化至关重要。 我们最近在动物模型中证明了我们可以量化纤维发生（活性疾病）无创。 使用分子磁共振（MR）探针GD-HYD，该探针靶向细胞外烯丙基，一种化学物质 氧化胶原蛋白的修饰，仅存在于活性纤维化期间。我们表明GD-HYD成像可以 检测纤维发生，监测治疗反应，并可以区分主动纤维发生与稳定的疤痕 肺和肝纤维化的模型。该项目的总体目标是改进该原型，以开发 优化的纤维发生MR探针可鲁棒，对患者的肝纤维发生定量。