Molecular Imaging of Liver Fibrosis

 描述（由申请人提供）：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，持续的损伤和修复循环导致富含纤维胶原的细胞外基质的积累，并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一个较小的阶段，甚至逆转到正常的结构。然而，如果不加以控制，纤维化将进展为肝硬化，估计影响世界人口的1-2%。肝硬化的主要临床后果是器官衰竭和肝细胞癌（HCC）的发展，并且全世界每年有超过一百万人死于肝硬化和HCC。胶原蛋白的积聚是肝纤维化的标志。出于这个原因，胶原蛋白沉积通过在肝活检中染色进行组织学评估，以便通过传统病理学方法对疾病进行评分。然而，活检是不完美的金标准，因为它可能导致并发症，遭受观察者内/观察者间的变异性，并且与采样误差相关。该提议的广泛的长期目标是开发体内分子成像探针，其可用于非侵入性地量化整个肝脏上的纤维化负荷和活性纤维化。我们最近报道了一种胶原靶向磁共振（MR）探针可以在标准四氯化碳中准确地量化纤维化负荷和分期肝纤维化 小鼠模型在这个项目中，我们不仅将扩大我们的研究与胶原蛋白靶向MR探针，但也测试了一种新的分子成像探针，检测赖氨酰氧化酶介导的胶原蛋白交联-一个特征的积极纤维化。特定目标I的目标是使用分子MR成像对几种动物模型中的纤维化进行非侵入性分期，因为肝纤维化是由各种不同的病因引起的。此外，基础肝纤维化的进展是肝衰竭和HCC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纤维化负荷和/或活跃的纤维化发生是否可以预测晚期肝脏结局，包括HCC。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，因为临床试验需要大量的患者人群接受长时间治疗才能达到具有临床意义的终点。Specific Aim III的目标是确定评估活跃纤维形成的成像生物标志物是否可用于建立更早的终点，这将使更大的候选疗法库能够进入关键临床试验。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形成，因此可以用于监测疾病进展和对治疗的反应。从这些实验中获得的数据将对数百万慢性肝病患者产生直接影响，并且应该具有广泛的影响，因为胶原蛋白沉积是器官纤维化的常见事件。

 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.