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.

Public Health Relevance

Liver fibrosis is the final common pathway for virtually all chronic liver diseases and is often a precursor to cirrhosis and hepatocellular carcinoma, devastating disorders that kill over a million people worldwide each year. Biopsy is currently the only method for assessing liver fibrosis but is not ideal due to its invasiveness, complications and high degree of sampling error. The goal of this project is to develop novel magnetic resonance imaging probes to non-invasively quantify liver fibrosis and active fibrogenesis in order to better monitor disease progression and response to antifibrotic therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK104956-04
Application #
9452959
Study Section
Clinical Molecular Imaging and Probe Development (CMIP)
Program Officer
Burgess-Beusse, Bonnie L
Project Start
2015-04-01
Project End
2020-03-31
Budget Start
2018-04-01
Budget End
2019-03-31
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
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