Ribosomes, the cellular factories responsible for making proteins, are essential for cell growth and division. Although a complete loss of ribosome biogenesis is expected to be lethal, dysfunctional ribosome biogenesis leads to a variety of human diseases. Recently, a missense mutation in the ribosome biogenesis protein, Cirhin, was reported to cause North American Indian childhood cirrhosis (NAIC). This suggests that ribosome biogenesis may be involved in other forms of cirrhosis, including alcoholic liver disease (ALD). The overall goal of this proposal is to examine the relationship between ribosome biogenesis and cirrhosis.
The first aim of this proposal is to identify novel proteins that are involved in ribosome biogenesis in liver cells by determining the protein interaction partners of Cirhin through both a yeast-two hybrid screen and affinity purification followed by mass spectrometery. One candidate protein, NOL11 has already been identified.
The second aim of this proposal is therefore to characterize any novel Cirhin-interacting proteins, including NOL11, and analyze their role in ribosome biogenesis. Finally, the third aim is to begin to elucidate the role of ribosome biogenesis in ALD. This will be accomplished by determining expression levels of ribosome biogenesis factors, including Cirhin, NOL11, and any other newly identified proteins, using immunofluorescence microscopy of liver tissue samples encompassing the whole spectrum of alcohol-induced liver injury. Since these proteins are required for ribosome biogenesis, their expression levels provide an easy indicator of whether ribosome biogenesis is occurring. Through these experiments, we will gain insight into how ribosome biogenesis affects both normal liver growth and the development of liver pathology.

Public Health Relevance

Liver cirrhosis is a major health problem in the United States, resulting in approximately 25,000 deaths per year, and increasing the risk of hepatocellular carcinoma, which has 22,000 new cases each year. Evidence suggests that dysfunctional ribosomes, the cellular factories that make proteins, may be involved in causing liver cirrhosis. Therefore, the goal of this proposal is to examine the relationship between liver cirrhosis and ribosome biogenesis.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31AA019842-02
Application #
8266016
Study Section
Health Services Research Review Subcommittee (AA)
Program Officer
Brooks, Pj
Project Start
2011-04-01
Project End
2012-05-31
Budget Start
2012-04-01
Budget End
2012-05-31
Support Year
2
Fiscal Year
2012
Total Cost
$5,988
Indirect Cost
Name
Yale University
Department
Genetics
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520