The outcomes of liver injury are dictated by the success or failure of repair. Current gaps in knowledge about how the liver regenerates limit prevention and treatment of cirrhosis and liver cancer, which are outcomes of dysfunctional regeneration (mis-repair).Thus, the ultimate goal of our research program is to delineate mechanisms that control liver regeneration. The present application seeks competitive renewal of a project that is evaluating the general hypothesis that the Hedgehog (Hh) pathway is one of the key regulators of liver regeneration. Thus far, we've discovered that the Hh pathway is activated during all types of liver injury, regulates multiple facets of regeneration, and that hepatic stellate cells (HSC) are critical targets of Hh signaling. We showed that acute injury transiently activates Hh signaling and proved this is required for regeneration. Conversely, we found that chronic injury provokes sustained Hh signaling that perpetuates phases of wound healing that necessitate mesenchymal cell enrichment and hence, fibrogenesis and liver cancer. The present application is built upon provocative evidence that HSC variably exhibit features of multipotent progenitors, liver epithelial cells, and myofibroblasts, and that Hh ligands modulate HSC fate decisions (i.e., reprogramming). Our latest data indicate that HSC reprogramming involves a Hh-regulated metabolic switch that induces glycolysis, and suggest that glycolytic end-products may modulate HSC fate. We will evaluate the SPECIFIC HYPOTHESIS that adult HSC retain sufficient plasticity to be reprogrammed to other lineages, and that Hh orchestrates liver regeneration by crafting a microenvironment that favors such reprogramming.
Our Aims are to answer these questions: 1) What is the role of the Hh signaling intermediate, Smoothened (Smo), in HSC reprogramming? 2) How do changes in intermediatry metabolism regulate Smo- mediated HSC reprogramming? 3) How do Hh-regulated changes in HSC phenotype impact liver regeneration and mis-repair. We will use transgenic mice that permit conditional deletion of Smo in quiescent or myofibroblastic-HSC before, during, and after liver injury.Preliminary data support the feasibility of this approach and link canonical Hh signaling with metabolic events that regulate HSC reprogramming.

Public Health Relevance

Liver cirrhosis and cancer are important causes of human suffering and death worldwide. Our work has identified previously-unsuspected mechanisms that control the development of these problems. These discoveries pave the way for new strategies to prevent and treat cirrhosis and liver cancer, which are the major bad outcomes of all types of chronic liver disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK077794-06
Application #
8485592
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Serrano, Jose
Project Start
2007-04-01
Project End
2016-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
6
Fiscal Year
2013
Total Cost
$329,524
Indirect Cost
$119,636
Name
Duke University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
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Machado, M V; Michelotti, G A; Pereira, T de Almeida et al. (2015) Reduced lipoapoptosis, hedgehog pathway activation and fibrosis in caspase-2 deficient mice with non-alcoholic steatohepatitis. Gut 64:1148-57
Guy, Cynthia; Suzuki, Ayako; Abdelmalek, Manal et al. (2015) Reply: To PMID 24849310. Hepatology 61:1770-1
Bohinc, Brittany N; Michelotti, Gregory; Xie, Guanhua et al. (2014) Repair-related activation of hedgehog signaling in stromal cells promotes intrahepatic hypothyroidism. Endocrinology 155:4591-601
Karaca, Gamze; Swiderska-Syn, Marzena; Xie, Guanhua et al. (2014) TWEAK/Fn14 signaling is required for liver regeneration after partial hepatectomy in mice. PLoS One 9:e83987
Swiderska-Syn, M; Syn, W K; Xie, G et al. (2014) Myofibroblastic cells function as progenitors to regenerate murine livers after partial hepatectomy. Gut 63:1333-44
Bohinc, Brittany; Michelotti, Gregory; Diehl, Anna Mae (2013) Hedgehog signaling in human medullary thyroid carcinoma: a novel signaling pathway. Thyroid 23:1119-26
Swiderska-Syn, Marzena; Suzuki, Ayako; Guy, Cynthia D et al. (2013) Hedgehog pathway and pediatric nonalcoholic fatty liver disease. Hepatology 57:1814-25
Xie, Guanhua; Karaca, Gamze; Swiderska-Syn, Marzena et al. (2013) Cross-talk between Notch and Hedgehog regulates hepatic stellate cell fate in mice. Hepatology 58:1801-13
Pereira, Thiago A; Xie, Guanhua; Choi, Steve S et al. (2013) Macrophage-derived Hedgehog ligands promotes fibrogenic and angiogenic responses in human schistosomiasis mansoni. Liver Int 33:149-61

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