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.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Predoctoral Individual National Research Service Award (F31)
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Health Services Research Review Subcommittee (AA)
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Brooks, Pj
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Yale University
Schools of Medicine
New Haven
United States
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Richardson, Lauren A; Reed, Benjamin J; Charette, J Michael et al. (2012) A conserved deubiquitinating enzyme controls cell growth by regulating RNA polymerase I stability. Cell Rep 2:372-85
Freed, Emily F; Prieto, José-Luis; McCann, Kathleen L et al. (2012) NOL11, implicated in the pathogenesis of North American Indian childhood cirrhosis, is required for pre-rRNA transcription and processing. PLoS Genet 8:e1002892