Chronic alcohol intake interferes with the onset and progression of liver regeneration after tissue damage, which is thought to contribute to the development of alcoholic liver disease. Our proposed studies will examine how the transcriptional regulatory network response after partial hepatectomy in the rat is affected by chronic alcohol intake. We will use a combination of experimental analysis of gene expression and transcription factor activity changes and computational modeling analysis to evaluate the impact on the transcriptional regulatory network that drive the regenerative response after partial hepatectomy in the rat. Our analysis will involve the following aims: (1) to analyze the temporal dynamics of the transcriptional profile derived from global gene expression data obtained from livers of control and chronically ethanol-fed rats, (2) to modulate the transcriptional network by experimental interventions employing in vivo delivery of small interfering RNAs (siRNAs) that target critical mediators and transcription factors and analyze the corresponding changes in the transcriptional network profile, specifically focusing on signals mediated by TNF-1 and the NF-:B network, and (3) developing a computational modeling approach to identify the major positive and negative feedback loops that control the network and drive the regenerative response. This computational analysis will then be used as a predictive tool to drive further experimental work and characterize the nature of the disruption of the response by chronic ethanol intake. We expect that this analysis will be able to provide novel insights that can do justice to the systemic nature of the regulatory network during liver regeneration and the deregulation of this network by the pleiotropic interactions caused by adaptation to long-term ethanol consumption.

Public Health Relevance

The goal of this project is to gain an in-depth understanding of the mechanisms by which chronic ethanol treatment interferes with the regenerative response to liver damage, which is thought to be a critical element in the susceptibility to alcoholic liver disease. This study will combine an experimental and computational modeling analysis of the temporal profile of gene expression changes and the underlying alterations in activity of transcription factors during the course of liver regeneration after partial hepatectomy in chronically ethanol-fed rats and their pair-fed controls.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA018873-04
Application #
8320424
Study Section
Special Emphasis Panel (ZAA1-JJ (06))
Program Officer
Radaeva, Svetlana
Project Start
2009-09-30
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
4
Fiscal Year
2012
Total Cost
$534,102
Indirect Cost
$188,404
Name
Thomas Jefferson University
Department
Pathology
Type
Schools of Medicine
DUNS #
053284659
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
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Antony, Anil Noronha; Paillard, Melanie; Moffat, Cynthia et al. (2016) MICU1 regulation of mitochondrial Ca(2+) uptake dictates survival and tissue regeneration. Nat Commun 7:10955
Kuttippurathu, Lakshmi; Patra, Biswanath; Hoek, Jan B et al. (2016) A novel comparative pattern count analysis reveals a chronic ethanol-induced dynamic shift in immediate early NF-κB genome-wide promoter binding during liver regeneration. Mol Biosyst 12:1037-56
Rouleau, Lauren; Antony, Anil Noronha; Bisetto, Sara et al. (2016) Synergistic effects of ascorbate and sorafenib in hepatocellular carcinoma: New insights into ascorbate cytotoxicity. Free Radic Biol Med 95:308-22
Kuttippurathu, Lakshmi; Juskeviciute, Egle; Dippold, Rachael P et al. (2016) A novel comparative pattern analysis approach identifies chronic alcohol mediated dysregulation of transcriptomic dynamics during liver regeneration. BMC Genomics 17:260
Correnti, Jason M; Cook, Daniel; Aksamitiene, Edita et al. (2015) Adiponectin fine-tuning of liver regeneration dynamics revealed through cellular network modelling. J Physiol 593:365-83
Nilakantan, Harshavardhan; Kuttippurathu, Lakshmi; Parrish, Austin et al. (2015) In Vivo Zonal Variation and Liver Cell-Type Specific NF-κB Localization after Chronic Adaptation to Ethanol and following Partial Hepatectomy. PLoS One 10:e0140236
Cook, Daniel; Ogunnaike, Babatunde A; Vadigepalli, Rajanikanth (2015) Systems analysis of non-parenchymal cell modulation of liver repair across multiple regeneration modes. BMC Syst Biol 9:71
Aksamitiene, Edita; Hoek, Jan B; Kiyatkin, Anatoly (2015) Multistrip Western blotting: a tool for comparative quantitative analysis of multiple proteins. Methods Mol Biol 1312:197-226
Cook, Daniel J; Patra, Biswanath; Kuttippurathu, Lakshmi et al. (2015) A novel, dynamic pattern-based analysis of NF-κB binding during the priming phase of liver regeneration reveals switch-like functional regulation of target genes. Front Physiol 6:189

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