Liver fibrosis represents the body's response to chronic liver injury and appears to be similar mechanistically to the fibrogenic response in other organs. The fibrogenic process is a complicated one, but at the same time, highly integrated. The pathobiology of fibrogenesis includes increased production of extracellular matrix proteins, tissue contraction, and ultimately, disruption of normal tissue structure architecture. It has been well established over the last 2 decades that in the liver, a key cellular effector of this processis the hepatic stellate cell. Hepatic stellate cells exhibit a further unique characteristic in that ater injury, they become activated and transform into a myofibroblast. This myofibroblastic transition is characterized not only by increased production of extracellular matrix (resulting in the fibrogenic response to injury), but also the expression of large quantities of the actin isoform, smooth muscle ? actin (also known as Acta2). The result of ongoing stellate cell activation and hepatic fibrogenesis is cirrhosis, which results in many serious clinical complications such as impaired hepatocellular function, hepatocellular carcinoma, portal hypertension with its associated disorders including ascites and gastrointestinal hemorrhage. Because of their central role in fibrogenesis and our goal to better understand the pathogenesis of liver fibrosis, specific area of investigation in our laboratory has been in the cell and molecular biology of hepatic stellate cells during the activation and wounding response. We have in particular been focused on the stellate cell myofibroblastic transition, and in this application focus on smooth muscle ? actin molecular biology - and its associated cell biology. Thus, in an effort to better understand smooth muscle ? actin biology in stellate cells, we have developed a series of tools, including ideal cell and animal systems that have allowed us to extend our work in a highly novel direction, to include exploration of the regulation of the stellate cell smooth muscle geneti program and the role of smooth muscle ? actin in fibrogenesis. The proposed studies have substantial implications for wound healing biology not only in the liver as well, but also in other organ systems. Finally, we propose a potential translational therapeutic approach as a result of the work with smooth muscle ? actin.

Public Health Relevance

Cirrhosis of the liver develops as the body's response to chronic liver injury. This injury may arise from any of many factors, including chronic hepatitis, fatty liver, alcohol, and many others. The liver responds to these injurious factors by scarring, which ultimately leads to cirrhosis. The goal of this application is to perform research that will allow us to better understand this scarring process. Since there is no current therapy to treat the scarring process of fibrosis, a further goal is to develop novel therapies that would allow us to better treat cirrhosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK098819-03
Application #
9042350
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Burgess-Beusse, Bonnie L
Project Start
2014-04-02
Project End
2018-03-31
Budget Start
2016-04-01
Budget End
2017-03-31
Support Year
3
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Medical University of South Carolina
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29403
Jophlin, Loretta L; Koutalos, Yiannis; Chen, Chunhe et al. (2018) Hepatic stellate cells retain retinoid-laden lipid droplets after cellular transdifferentiation into activated myofibroblasts. Am J Physiol Gastrointest Liver Physiol 315:G713-G721
Shi, Zengdun; Rockey, Don C (2017) Upregulation of the actin cytoskeleton via myocardin leads to increased expression of type 1 collagen. Lab Invest 97:1412-1426
Ansa-Addo, Ephraim A; Zhang, Yongliang; Yang, Yi et al. (2017) Membrane-organizing protein moesin controls Treg differentiation and antitumor immunity via TGF-? signaling. J Clin Invest 127:1321-1337
Rockey, Don C (2016) Liver Fibrosis Reversion After Suppression of Hepatitis B Virus. Clin Liver Dis 20:667-679
Singh, Shweta; Liu, Songling; Rockey, Don C (2016) Caveolin-1 is upregulated in hepatic stellate cells but not sinusoidal endothelial cells after liver injury. Tissue Cell 48:126-32
Rockey, Don C (2015) Endothelial dysfunction in advanced liver disease. Am J Med Sci 349:6-16
Kim, Seok-Hyung; Wu, Shu-Yu; Baek, Jeong-In et al. (2015) A post-developmental genetic screen for zebrafish models of inherited liver disease. PLoS One 10:e0125980
Sajja, Krishna C; Mohan, Desh P; Rockey, Don C (2014) Age and ethnicity in cirrhosis. J Investig Med 62:920-6