Abstract

TNFalpha- and Fas-induced apoptosis in the liver in experimental animals in closely associated with liver in disease in patients. We have developed a model systems to study apoptosis in primary cultures of hepatocytes. We wish to assess the role of NFkappaB in the apoptotic pathways induced by TNFalpha and Fas. The underlying hypothesis is that NF-kappaB is anti-apoptotic via the induction of genes that affect DISC (Death-Inducing Signaling Complex) formation, the mitochondrial permeability transition (MPT), and caspase activation. This proposal wishes to examine the following specific aims: 1. To assess the effect of NF-kappaB on the apoptotic signaling pathways mediated by TNFalpha and Fas. 2. To determine which genes are induced by NFkappaB in response to TNFalpha and Fas in cultured hepatocytes. 3. To demonstrated a protective role for NO and iNOS in TNFalpha- and Fas-mediated apoptosis in hepatocytes. 4. To test the requirement of GD3 in TNFalpha- and Fas-mediated apoptosis in hepatocytes. It is the balance between these anti-apoptotic and apoptotic signals that determines the fate of the hepatocyte in this pathophysiological process.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
1P01DK059340-01
Application #
6357643
Study Section
Special Emphasis Panel (ZDK1)
Project Start
2000-12-01
Project End
2005-11-30
Budget Start
Budget End
Support Year
1
Fiscal Year
2001
Total Cost
Indirect Cost

  Institution

Name
University of North Carolina Chapel Hill
Department
Type
DUNS #
078861598
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599

  Publications

Dolganiuc, Angela; Thomes, Paul G; Ding, Wen-Xing et al. (2012) Autophagy in alcohol-induced liver diseases. Alcohol Clin Exp Res 36:1301-8
Kim, Insil; Lemasters, John J (2011) Mitochondrial degradation by autophagy (mitophagy) in GFP-LC3 transgenic hepatocytes during nutrient deprivation. Am J Physiol Cell Physiol 300:C308-17
Kim, Insil; Lemasters, John J (2011) Mitophagy selectively degrades individual damaged mitochondria after photoirradiation. Antioxid Redox Signal 14:1919-28
Rodriguez-Enriquez, Sara; Kai, Yoichiro; Maldonado, Eduardo et al. (2009) Roles of mitophagy and the mitochondrial permeability transition in remodeling of cultured rat hepatocytes. Autophagy 5:1099-106
Kim, Insil; Rodriguez-Enriquez, Sara; Lemasters, John J (2007) Selective degradation of mitochondria by mitophagy. Arch Biochem Biophys 462:245-53
Adachi, Masayuki; Osawa, Yosuke; Uchinami, Hiroshi et al. (2007) The forkhead transcription factor FoxO1 regulates proliferation and transdifferentiation of hepatic stellate cells. Gastroenterology 132:1434-46
Lemasters, John J (2007) Modulation of mitochondrial membrane permeability in pathogenesis, autophagy and control of metabolism. J Gastroenterol Hepatol 22 Suppl 1:S31-7
Hammond, Linda E; Albright, Craig D; He, Lihua et al. (2007) Increased oxidative stress is associated with balanced increases in hepatocyte apoptosis and proliferation in glycerol-3-phosphate acyltransferase-1 deficient mice. Exp Mol Pathol 82:210-9
Rodriguez-Enriquez, Sara; Kim, Insil; Currin, Robert T et al. (2006) Tracker dyes to probe mitochondrial autophagy (mitophagy) in rat hepatocytes. Autophagy 2:39-46
Lemasters, John J; Holmuhamedov, Ekhson (2006) Voltage-dependent anion channel (VDAC) as mitochondrial governator--thinking outside the box. Biochim Biophys Acta 1762:181-90

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