The underlying hypothesis of this proposal is that the impaired wound healing that occurs in patients with cachexia results from the profound effects of excessive tumor necrosis factor alpha (TNFa) on extracellular matrix proteins. TNFa is known to inhibit fibrillar collagen expression and to stimulate interstitial collagenase (MMP-1) expression. TNFa is a potent activator of the stress activated protein kinase (SAPK/JNK), an activator of c-JUN that in turn is the principal transcription factor stimulating the collagenase gene.
The aims of this proposal are: 1) To determine which TNFa receptor is responsible for the upregulation of collagenase and the downregulation of collagen. 2) To determine the role of ceramide in the stimulation of SAPK/JNK by TNFa. 3) To determine the intermediate steps by which TNFa activates SAPK/JNK. 4) To determine the signal transduction pathway by which TNFa inhibits type I collagen gene expression. 5) To assess potential inhibitors of TNFa signal transduction. Most of the experiments will use cultures of normal human fibroblasts, but selected experiments will involve use of mouse fibroblasts for the purpose of establishing stable transfectants. HL-60 cells will be used to examine the role of ceramide in regulating the extracellular matrix.
| Tripathi, Anupriya; Debelius, Justine; Brenner, David A et al. (2018) The gut-liver axis and the intersection with the microbiome. Nat Rev Gastroenterol Hepatol 15:397-411 |
| Vollmann, Elisabeth H; Cao, Lizhi; Amatucci, Aldo et al. (2017) Identification of Novel Fibrosis Modifiers by In Vivo siRNA Silencing. Mol Ther Nucleic Acids 7:314-323 |
| Koyama, Yukinori; Wang, Ping; Liang, Shuang et al. (2017) Mesothelin/mucin 16 signaling in activated portal fibroblasts regulates cholestatic liver fibrosis. J Clin Invest 127:1254-1270 |
| Kim, In Hee; Kisseleva, Tatiana; Brenner, David A (2015) Aging and liver disease. Curr Opin Gastroenterol 31:184-91 |
| Lan, Tian; Kisseleva, Tatiana; Brenner, David A (2015) Deficiency of NOX1 or NOX4 Prevents Liver Inflammation and Fibrosis in Mice through Inhibition of Hepatic Stellate Cell Activation. PLoS One 10:e0129743 |
| Brenner, David A; Paik, Yong-Han; Schnabl, Bernd (2015) Role of Gut Microbiota in Liver Disease. J Clin Gastroenterol 49 Suppl 1:S25-7 |
| Paik, Yong-Han; Kim, Jonghwa; Aoyama, Tomonori et al. (2014) Role of NADPH oxidases in liver fibrosis. Antioxid Redox Signal 20:2854-72 |
| Liu, Cheng; Chen, Xiaorong; Yang, Ling et al. (2014) Transcriptional repression of the transforming growth factor ? (TGF-?) Pseudoreceptor BMP and activin membrane-bound inhibitor (BAMBI) by Nuclear Factor ?B (NF-?B) p50 enhances TGF-? signaling in hepatic stellate cells. J Biol Chem 289:7082-91 |
| Iwaisako, Keiko; Jiang, Chunyan; Zhang, Mingjun et al. (2014) Origin of myofibroblasts in the fibrotic liver in mice. Proc Natl Acad Sci U S A 111:E3297-305 |
| Madsen, Daniel H; Leonard, Daniel; Masedunskas, Andrius et al. (2013) M2-like macrophages are responsible for collagen degradation through a mannose receptor-mediated pathway. J Cell Biol 202:951-66 |
Showing the most recent 10 out of 115 publications
