Molecular Imaging of Liver Fibrosis

 描述(申请人提供)：肝纤维化是几乎所有慢性肝损伤的共同结果。在纤维化过程中，正在进行的损伤和修复循环导致富含纤维状胶原的细胞外基质积聚，最终破坏正常的组织结构和功能。如果疾病的根本原因被抑制或及早消除，肝纤维化有可能倒退到较小的阶段，甚至逆转到正常的结构。然而，如果不加以控制，纤维化将发展为肝硬变，据估计，这是一种晚期疾病，影响世界人口的1-2%。肝硬变的主要临床后果是器官衰竭和肝细胞癌的发展，全世界每年有超过100万人死于肝硬变和肝细胞癌。胶原蛋白的堆积是肝纤维化的一个标志。因此，胶原蛋白的沉积是通过肝活检的染色进行组织学评估的，以便通过传统的病理学方法对疾病进行评分。然而，活组织检查是一个不完善的金标准，因为它可能会导致并发症，存在观察者内/观察者间的变异性，并与采样误差有关。这一建议的广泛、长期目标是开发可用于非侵入性量化整个肝脏的纤维负担和活跃的纤维形成的活体分子成像探针。我们最近报道，在标准的四氯化碳中，胶原靶向磁共振(Mr)探针可以准确地量化纤维化负担和分期肝纤维化。 老鼠模型。在这个项目中，我们不仅将扩展我们对胶原靶向磁共振探针的研究，还将测试一种新的分子成像探针，该探针可以检测赖氨酰氧化酶介导的胶原交联--这是活动性纤维化的特征。具体目标I的目标是利用分子磁共振成像在几种动物模型中非侵入性地分期纤维化，因为肝纤维化是由各种不同的病因引起的。此外，肝纤维化的进展是肝功能衰竭和肝细胞癌的最大危险因素。因此，特定目标II的目标是确定在早期时间点评估肝纤维化负担和/或活动性肝纤维化是否可以预测包括肝细胞癌在内的晚期肝脏结局。一些抗纤维化药物开始进入临床试验。由于疾病进展缓慢，这些药物的开发存在巨大的成本风险，因为临床试验需要长期治疗的大量患者群体才能达到临床上有意义的终点。具体目标III的目的是确定是否可以使用评估活动性纤维化的成像生物标记物来建立更早的终点，从而使更多的候选疗法进入关键的临床试验。我们的假设是，胶原和赖氨酰氧化酶介导的胶原交联的分子成像将准确地反映纤维化负担和活跃的纤维化形成，因此可以用于监测疾病进展和治疗反应。从这些实验中获得的数据将对数百万患有慢性肝病的人产生直接影响，并应具有广泛的影响，因为胶原沉积是器官纤维化中的常见事件。

 DESCRIPTION (provided by applicant): Liver fibrosis is the common result of virtually all chronic liver injuries. During fibrosis, the ongoing cycles of injury and repair lead to accumulation of extracellular matrix rich in fibrillar collagen and eventually disruption of the normal tissue architecture and function. If the underlying cause of disease is suppressed or removed early enough, liver fibrosis has the potential to regress to a lesser stage or even reverse to a normal architecture. However, if left unchecked, fibrosis will progress to cirrhosis, an advanced stage of the disease estimated to affect 1-2% of the world's population. The major clinical consequences of cirrhosis are organ failure and development of hepatocellular carcinoma (HCC), and over a million people worldwide die each year from cirrhosis and HCC. Accumulation of collagen is a hallmark of liver fibrosis. For this reason, collagen deposition is assessed histologically by staining in liver biopsies in order to score disease by traditional pathology methods. However, biopsy is an imperfect gold standard as it can lead to complications, suffers from intra/inter-observer variability, and is associated with sampling error The broad, long-term objective of this proposal is to develop in vivo molecular imaging probes that can be used to non-invasively quantify fibrotic burden and active fibrogenesis over the entire liver. We have recently reported that a collagen-targeted magnetic resonance (MR) probe can accurately quantify fibrotic burden and stage liver fibrosis in a standard carbon tetrachloride mouse model. In this project, we will not only expand upon our studies with the collagen- targeted MR probe but also test a new molecular imaging probe that detects lysyl oxidase-mediated collagen crosslinking - a characteristic of active fibrogenesis. The goal of Specific Aim I is to non-invasively stage fibrosis in several animal models using molecular MR imaging as liver fibrosis results from a variety of different etiologies. In addition, progression of underlyig liver fibrosis is the greatest risk factor for liver failure and HCC. The goal of Specific Aim II therefore is to determine whether assessments of fibrotic burden and/or active fibrogenesis at early time points can predict late-stage liver outcomes including HCC. A few antifibrotic drugs are starting to move into clinical trials. Because disease progression is slow, there is an enormous cost risk to development of these drugs, since clinical trials require large patient populations treated for long periods of time to reach a clinically significant endpoint. The goal o Specific Aim III is to determine whether an imaging biomarker that assesses active fibrogenesis could be used to establish an earlier endpoint which would enable a much larger pool of candidate therapies to move into pivotal clinical trials. Our hypothesis is that molecular imaging of collagen and lysyl oxidase-mediated collagen crosslinking will accurately reflect fibrotic burden and active fibrogenesis and thus can be used to monitor disease progression and response to therapy. The data obtained from these experiments will have immediate impact on the millions of people living with chronic liver disease and should have broad implications as collagen deposition is a common event in organ fibrosis.