ARRA Investments in Chronic Liver Disease
Public Health Burden
According to the Centers for Disease Control and Prevention, chronic liver disease and cirrhosis is the twelfth leading cause of death in the U.S. Chronic liver disease can result from multiple causes, such as hepatitis B and C, alcoholic and nonalcoholic fatty liver disease (NAFLD), genetic conditions and autoimmune liver diseases. The major adverse outcome of chronic liver disease is the development of cirrhosis and end-stage liver disease, which are the major reasons for liver transplantation.
Basic Mechanisms of Liver Fibrosis, Cirrhosis, and Portal Hypertension
The development of cirrhosis during the course of chronic liver disease is a gradual process of increasing liver fibrosis, in which healthy tissue is replaced with scar tissue, which leads to stiffening of the liver, as well as portal hypertension (increased blood pressure in the portal vein supplying blood to the liver). ARRA funding will enhance understanding of these processes and translate this to clinical care:
A project will study immune cell activation of stellate cell enzymes called matrix metalloproteinases, which break down scar tissue and can reverse fibrosis and potentially improve already established cirrhosis.
A project will build on knowledge of liver fibrosis pathways to develop new treatments for liver fibrosis by screening peptides with activity as inhibitors of the C/EBP beta protein, which plays a central role in fibrosis development.
A project will test an ultrasound technique to noninvasively measure portal hypertension, to allow for accurate diagnosis and improved monitoring of treatment response without the need for the invasive and expensive techniques that are now required to measure portal pressure.
Animal Models of Human Liver Diseases
Common causes of chronic liver disease include hepatitis C, nonalcoholic fatty liver diseases such as nonalcoholic steatohepatitis (NASH), and inherited metabolic diseases. For chronic hepatitis C, the major cause of chronic liver disease in the U.S., no means of prevention is available, and response to standard treatment occurs in only half of patients. Currently, studies of new treatments for hepatitis C must be carried out in humans or in chimpanzees, the only accurate animal model in which to study this infection. To better understand disease processes and find new treatments requires small animal models that accurately mimic human liver diseases, such as those proposed in ARRA-funded projects:
A project will try to develop a small animal (mouse) model to study mechanisms of hepatitis C virus infection and test prevention and therapeutic strategies.
A project will try to identify genetic factors that contribute to NAFLD and NASH, and the mechanisms by which they influence these disease processes, using mouse models.
A project will try to create animal models with “humanized” livers, in which mouse cells are replaced with human cells, which can be used to identify treatments for inborn errors of human liver function.
Iron overload occurs in hemochromatosis, in which excess iron is stored in organs such as the liver, damaging them to the point that they no longer work properly. Congenital hemochromatosis has been found to be caused by mutations in the
gene. Neonatal hemochromatosis has recently been shown to be caused by maternal immune reactions to the fetal liver and is highly fatal unless treated rapidly, which can only occur if a diagnosis is made in time to prevent death from liver failure. ARRA-supported awards are investigating mechanisms underlying hemochromatosis and how to improve care:
A project will enhance understanding of the function of the HFE protein in affecting iron status to cause iron overload in patients with hereditary hemochromatosis.
A project will investigate biochemical processes regulating iron homeostasis and test two small molecules that inhibit iron transport processes as possible therapies for hemochromatosis.
A project will improve diagnosis and timely treatment of neonatal hemochromatosis in young infants with acute liver failure using a test for a new biomarker of this disease in infant serum.
Drug-Induced Liver Injury
Drug-induced liver injury has emerged in recent years as an important cause of liver failure in the United States, which jeopardizes public health and limits the success of drug development processes. Studies funded by ARRA are pursuing new research directions to identify those most at risk for this liver injury:
A clinical research project, including a genome-wide association study, will assess the role of genetic factors in drug-induced liver injury.
A project will evaluate use of a newly developed mouse model population for detecting genetic susceptibility factors that predispose individuals to drug-induced liver injury.
Advanced Liver Disease
For advanced forms of liver disease, such as cirrhosis and liver cancer, the only effective treatment available is often liver transplantation. ARRA-funded research on advanced liver disease includes:
Identifying new markers of the development of hepatocellular carcinoma through genomic and proteomic approaches, for use in early diagnosis and screening approaches.
Designing an improved system for equitably allocating donor livers for transplantation throughout geographic regions of the U.S., and estimating its impact on patient outcomes and healthcare costs.
-- Fibrolytic Activation of Hepatic Stellate Cells by T Cell Derived Microparticles -- Schuppan, Detlef (MA)
-- C/EBP beta Peptides for the Treatment of Hepatic Fibrosis -- Buck, Martina (contact); Chojkier, Mario (CA)
-- Noninvasive and Accurate Measurement of Portal Hypertension -- Forsberg, Flemming (PA)
-- An Inbred Mouse Model for HCV Infection, Immunity, and Pathogenesis -- Rice, Charles (NY)
-- Molecular and Genetic Analysis of Murine Steatohepatitis -- Green, Richard (IL)
-- Modeling Liver Metabolism with Patient-specific iPS Derived Hepatocytes -- Duncan, Stephen (contact); Grompe, Markus (WI)
-- Function of the Hemochromatosis Protein -- Enns, Caroline (OR)
-- Ferristatin: A New Small Molecule Inhibitor of Iron Transport -- Wessling-Resnick, Marianne (MA)
--Serologic Test for Neonatal Hemochromatosis in Infants with Acute Liver Failure--Whitington, Peter (IL)
-- Coordinating Center for the Drug Induced Liver Injury Network (DILIN) -- Rochon, James (NC)
-- Revolutionizing Preclinical Detection of Risk Factors for Idiosyncratic Drug-indu -- Threadgill, David (NC)
-- Novel Markers for HCV-related HCC -- Beretta, Laura (WA)
--Reducing Geographic Disparity in Transplant Access:Clinical and Economic Impact--Lentine, Krista(MO)
Page Last Updated on June 30, 2018
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