Liver fibrosis/cirrhosis is a global health problem and one of the leading causes of morbidity and mortality in the world. Alcohol abuse is one of the most common causes of liver fibrosis/cirrhosis in western developed countries, accounting for more than 50% of cirrhosis cases. Alcoholic liver fibrogenesis is a complicated process involving many cytokines, and unfortunately, there is no standard treatment for liver fibrosis till now. Whil liver fibrosis is reversible and treatable, if left untreated, it will develop to the end stage, lier cirrhosis, which is irreversible and untreatable. Therefore, effective antifibrotic medicines are needed urgently. Our strategy is to reverse the over-produced type I collagen which is formed at the end of fibrogenesis. It is the most critical step toward the effective therapy of alcoholic livr fibrosis because the accumulated type I collagen in fibrotic liver has to be reversed no matter what treatment is employed. We proposed siRNA to silence the PCBP2 gene expression, subsequently leading to destabilization of the collagen ?1(I) mRNA and eventually the reversal of the accumulated type I collagen. Recently, we have proved that alcohol up-regulates the expression of PCBP2 in Hepatic Stellate Cells (HSCs). Moreover, we have identified a siRNA that can silence the PCBP2 gene and subsequently increase the decay rate of collagen ?1(I) mRNA in HSCs. The research outlined in the current proposal has been designed specifically to treat alcoholic liver fibrosis in experimental animals via blocking the expression of PCBP2 using a targeted siRNA nanocomplex. The overall objectives in the application are two-fold: 1) to develop the avidin-based nanocomplex to overcome the two potential obstacles (poor stability and lack of target-ability to HSCs) of PCBP2 siRNA;2) to evaluate its therapeutic effectiveness using various in vitro and in vivo models. Our central hypothesis is that the reversal of the accumulated type I collagen is critical in treatment of alcoholic liver fibrosis. Accomplishments o our proposed studies are expected to provide an evidence-based foundation for development of other siRNA therapeutics for liver diseases.

Public Health Relevance

Liver fibrosis/cirrhosis is a global health problem and one of the leading causes of morbidity and mortality in the world. Alcohol abuse is one of the most common causes of liver fibrosis/cirrhosis in western developed countries, accounting for more than 50% of cirrhosis cases. Successful accomplishment of this project will provide an effective siRNA therapy to treat alcoholic liver fibrosis by inducing degradation of the accumulated type I collagen.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01AA021510-03
Application #
8716618
Study Section
Nanotechnology Study Section (NANO)
Program Officer
Radaeva, Svetlana
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Missouri Kansas City
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
City
Kansas City
State
MO
Country
United States
Zip Code
64110
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