It is my long term goal to become an independent investigator and study the pathogenesis of liver disease including alcoholic liver disease. Obtaining a K01 grant would be an important step for me to become an independent researcher since it will provide me an opportunity and time to overcome many weaknesses (lack of preliminary data and publications in alcohol research, previous lack of focus on a clinically important model system, inexperience in cell signaling, cell imaging, and molecular biology techniques) in my background to become competitive for an R01 in alcohol research in the near future. By providing my salary and research funding, the K01 grant will free me from working on other PIs'projects and allow me to really focus on alcohol, as well as become more experienced in cell signaling, cell imaging, and molecular biology. The area of science I have chosen to pursue in the upcoming period is at the interface of redox biology, signal transduction and hepatotoxicity using alcohol as a model of liver injury. TNF-induced damage to hepatocytes remains a central point in alcohol-induced liver damage. Recent evidence from our laboratory suggests that redox alterations through GSH modulation or oxidant treatment sensitize hepatocytes to TNF-induced apoptosis by inhibiting NF-?B transcriptional activity. This suggests a link between TNF secretion and redox alterations in mediating damage to liver. The hypothesis to be tested is that redox alterations caused by alcohol sensitize hepatocytes to TNF-induced apoptosis through inhibition of NF-?B dependent signaling pathways. The hypothesis will be tested with the following specific aims: 1) Determine how alcohol-induced alterations of cellular redox status modulates NF-?B signaling and TNF-induced apoptosis in cultured primary hepatocytes. The question of whether alcohol-induced redox changes inhibit NF-?B dependent gene expression in the presence of TNF in cultured primary hepatocytes will be explored. 2) Determine the effect of chronic alcohol consumption on hepatic redox status, NF-?B redox status, NF-?B signaling pathways, N binding to DNA, and NF-?B dependent gene expression in liver. The relationship between NF-?B signaling and redox status will be explored following chronic alcohol treatment in vivo. A focus of this application is to utilize imaging techniques (e.g., confocal microscopy, flow cytometry) to study redox status and NF-?B signaling simultaneous in the same cell. These methods will allow me to assess possible heterogeneity in redox status and NF-?B signaling that alcohol may induce to the hepatocyte population. The outcome of these studies will provide new insights into the mechanism by which alcohol causes liver damage. Public Health Relevance: The outcome of these studies will provide new insights into the mechanism by which alcohol causes liver damage. The findings of this application may shed light on new therapeutic strategies involving thiol antioxidants for prevention or treatment of alcohol related diseases.
|Saberi, Behnam; Ybanez, Maria D; Johnson, Heather S et al. (2014) Protein kinase C (PKC) participates in acetaminophen hepatotoxicity through c-jun-N-terminal kinase (JNK)-dependent and -independent signaling pathways. Hepatology 59:1543-54|
|Han, Derick; Dara, Lily; Win, Sanda et al. (2013) Regulation of drug-induced liver injury by signal transduction pathways: critical role of mitochondria. Trends Pharmacol Sci 34:243-53|
|Win, Sanda; Than, Tin Aung; Han, Derick et al. (2011) c-Jun N-terminal kinase (JNK)-dependent acute liver injury from acetaminophen or tumor necrosis factor (TNF) requires mitochondrial Sab protein expression in mice. J Biol Chem 286:35071-8|
|Shinohara, Mie; Ybanez, Maria D; Win, Sanda et al. (2010) Silencing glycogen synthase kinase-3beta inhibits acetaminophen hepatotoxicity and attenuates JNK activation and loss of glutamate cysteine ligase and myeloid cell leukemia sequence 1. J Biol Chem 285:8244-55|
|Garcia, Jerome; Han, Derick; Sancheti, Harsh et al. (2010) Regulation of mitochondrial glutathione redox status and protein glutathionylation by respiratory substrates. J Biol Chem 285:39646-54|
|Jones, Dean P; Lemasters, John J; Han, Derick et al. (2010) Mechanisms of pathogenesis in drug hepatotoxicity putting the stress on mitochondria. Mol Interv 10:98-111|
|Yap, Li-Peng; Garcia, Jerome V; Han, Derick et al. (2009) The energy-redox axis in aging and age-related neurodegeneration. Adv Drug Deliv Rev 61:1283-98|