Liver disease is a significant human health concern arising from diverse pathologies including drug overdose, alcoholism, infectious diseases, metabolic disorders, idiopathic causes, and cancer. The majority of the millions of Americans affected by these illnesses have poor therapeutic options. Pharmacologic interventions to enhance the restorative ability of the liver are desperately needed. They promise wide applicability for patients with chronic and acute liver disease. Patients with chronic liver disease often experience profound debilitation and inexorable progression of their disease. Treatments to enhance the ability of the liver to repair itself will ameliorate symptoms, prolong life, and obviate the need for liver transplantation. Patients with acute liver failure need short-term therapies to boost liver repair and allow recovery. Drugs to enhance liver repair have the potential to transform a patient death or need for liver transplantation into a complete cure. The goal of this proposal is develop drugs and methods to treat human liver disease. We seek to enhance the natural ability of the liver to repair itself. We will accomplish this by building on our preliminary studies that 1) identified a novel and modifiable signaling pathway critical for liver repair 2) demonstrated that drugs that affect this pathway enhance liver repair, cementing the clinical promise of our approach, and 3) developed novel methodology that allows unprecedented ability to manipulate genes in the liver and therefore ask fundamental research questions. This proposal will investigate three fundamental questions. First, we will identify specific molecules in the pathway that we discovered that are critical during liver repair. These studies are essential to understand the system and guide drug development. Next, we will determine the mechanism by which this pathway affects liver repair. These studies will reveal fundamental paradigms of liver repair and help predict how drugs which stimulate these mechanisms will affect patients. Finally, we will directly evaluate drugs that influence this pathway in a variety of liver injury models with direct relevance to human disease.

Public Health Relevance

Liver disease is a national health problem with over 5 million people at risk for chronic liver disease, and 20,000 patients each year who suffer from acute liver failure. Despite these sobering numbers, therapeutic options are dismal--new therapies are desperately needed. This purpose of this proposal is to build on our previous work which identified drugs that enhance the ability to repair itself after injury and develop therapies for human liver disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
3R01DK081387-04S1
Application #
8586789
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Serrano, Jose
Project Start
2010-04-20
Project End
2015-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
4
Fiscal Year
2013
Total Cost
$1,500
Indirect Cost
$538
Name
Vanderbilt University Medical Center
Department
Surgery
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Tsugawa, Daisuke; Oya, Yuki; Masuzaki, Ryota et al. (2014) Specific activin receptor-like kinase 3 inhibitors enhance liver regeneration. J Pharmacol Exp Ther 351:549-58
Ho, Karen J; Do, Nhue L; Otu, Hasan H et al. (2010) Tob1 is a constitutively expressed repressor of liver regeneration. J Exp Med 207:1197-208