Identification of New Therapeutic Strategies for Targeting Liver Fibrosis
Abstract
Liver disease is a condition characterized by progressively deteriorating liver function. Chronic liver damage first leads to fibrosis of the liver, a condition in which collagen is deposited in the liver causing damage and death to hepatocytes. If left untreated, through repeated cycles of damage this condition can continue to liver cirrhosis and ultimately may lead to hepatocellular carcinoma. Currently, Hepatitis B and C are the leading causes of liver disease, although in the coming decade it is expected that non-alcoholic fatty liver disease will replace viral hepatitis as the most common cause of liver disease. This proposal address the Topic Area of Hepatitis B and liver fibrosis. In this work, we will develop a novel platform to identify therapies to reverse fibrosis, an area of emphasis for this award mechanism. DNA is wrapped around proteins called histones to form chromatin. Packaging into chromatin allows each cell to store the roughly 2 meters of DNA in an orderly manner inside the cell. However, chromatin is not simply a storage molecule, and its structure can play critical regulatory roles. Any molecule or process that requires access to the DNA will require changes to chromatin. These changes are common throughout development of an organism, and recent work, particularly in cancer studies, has demonstrated the vital role of chromatin in normal cell function. During the progression of liver disease, the liver undergoes drastic changes in function involving multiple cell types responding to various external cues. We hypothesize that these changes induce alterations to chromatin that could be targeted as treatments of the disease. Therefore, disruption of chromatin regulation may be a link between multiple forms of liver disease, making the proteins involved in this regulation an excellent class of new therapeutic targets. In this proposal, we will develop novel treatment strategies that focus on chromatin-regulating proteins. Using a novel screening approach in both cell culture and animal models of fibrosis, we will identify which chromatin regulators are important for the establishment or progression of fibrosis. This will be the first example of a high-throughput screen in an animal model for liver fibrosis. We focus on specific cell types important in generating collagen, and on proteins that regulate chromatin. Establishment and validation of our approach could then be applied to other families of proteins, or to other cell types, in future studies expanding the therapeutic targets of liver disease and increasing the likelihood of successful translation.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010636
Entities
People
- Jesse R Raab
Organizations
- United States Army
- University of North Carolina at Chapel Hill