Liver disease is a common cause of morbidity and mortality in the United States. Delineating the critical pathways involved in liver development is essential for our knowledge of normal liver function and the maintenance of tissue homeostasis. Disturbances in liver development can lead to severe malformations of the hepatobiliary system and hepatic neoplasia. Additionally, the liver is exposed to both environmental and endogenous toxins, necessitating ongoing repair and regeneration. Wnt signaling influences cellular proliferation and differentiation in several endodermal organs as well as ongoing repair in the adult. Using the zebrafish (Danio rerio) model, we have successfully elucidated a highly specific regulatory role for wnt signaling in both liver development and regeneration. We have further discovered that the positive effect of enhanced wnt activity on organ regeneration following injury is conserved across vertebrate species. Additionally, using zebrafish, we interrogated the functional requirement of conserved modifiers of wnt activity in vivo. The complex interactions between the Wnt signaling pathway and other critical regulators of liver formation, function and regeneration, however, remain largely undefined. Here, I plan extend my original K08 investigation to characterize the functional relationship to a clinically relevant modifier of wnt activity, PGE2. In the first Specific Aim, I seek to determine the mechanism by which PGE2 influences wnt-mediated liver specification and growth. In the second Specific Aim, I will investigate the coordinate regulatory effects of PGE2 and the wnt signaling pathway on liver regeneration following injury. These studies will provide insight into the basic mechanisms of liver differentiation and growth, and will help to identify potential therapeutic targets to improve liver regeneration and cancer therapy. Funding through the R03 Small Grants Program will be essential to the completion of the work outlined in this proposal;in addition to defraying the cost of technical assistance, grant money will be utilized to directly fund experiments that might otherwise be too costly to conduct now that I have begun the transition to becoming an independent investigator.

Public Health Relevance

Liver disease is a common cause of illness and death in the United States. Metabolic disturbances, cirrhosis, viral infection, drug overdose and carcinogenesis can all lead to liver failure and the need for surgical resection or transplantation. This study seeks to identify factors regulating liver specification and growth that can be utilized as rational targets for novel therapeutic strategies to facilitate liver regeneration or inhibit cancer progression.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Small Research Grants (R03)
Project #
1R03DK085445-01
Application #
7773834
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Podskalny, Judith M,
Project Start
2010-03-01
Project End
2012-02-29
Budget Start
2010-03-01
Budget End
2011-02-28
Support Year
1
Fiscal Year
2010
Total Cost
$89,000
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
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Shan, Jing; Schwartz, Robert E; Ross, Nathan T et al. (2013) Identification of small molecules for human hepatocyte expansion and iPS differentiation. Nat Chem Biol 9:514-20
Cutler, Corey; Multani, Pratik; Robbins, David et al. (2013) Prostaglandin-modulated umbilical cord blood hematopoietic stem cell transplantation. Blood 122:3074-81