Effects of BLT1 inhibition in a mouse model of liver fibrosis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1043143 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26893800_1.fastq.gz | Fastqsanger.gz | |||
| SRR26893800_2.fastq.gz | Fastqsanger.gz | |||
| SRR26893801_1.fastq.gz | Fastqsanger.gz | |||
| SRR26893801_2.fastq.gz | Fastqsanger.gz | |||
| SRR26893802_1.fastq.gz | Fastqsanger.gz |
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Project description:Non-alcoholic fatty liver disease (NAFLD) is a leading form of chronic liver disease with large unmet need. Non-alcoholic steatohepatitis (NASH), a progressive variant of NAFLD, can lead to fibrosis, cirrhosis, and hepatocellular carcinoma. To identify potential new therapeutics for NASH, we used a computational approach based on Connectivity Map (CMAP) analysis, which pointed us to a potential application of bromodomain and extra-terminal motif (BET) inhibitors for treating NASH. To experimentally validate this hypothesis, we tested a small-molecule inhibitor of the BET family of proteins, GSK1210151A (I-BET151), in the STAM mouse NASH model at two different dosing timepoints (onset of NASH and onset of fibrosis) to assess its potential effectiveness for the treatment of NASH and liver fibrosis. I-BET151 decreased the non-alcoholic fatty liver disease activity score (NAS), a clinical endpoint for assessing the severity of NASH, as well as progression of liver fibrosis and interferon-γ expression. Transcriptional characterization through RNA-sequencing pointed to alterations in molecular mechanisms related to interferon signaling and cholesterol biosynthesis following treatment, as well as reversal of gene expression patterns linked to fibrotic markers. Altogether, these results suggest that inhibition of BET proteins may present a novel therapeutic opportunity in the treatment of NASH and liver fibrosis.
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Project description:To confirm the mechanism of miR-29a in liver fibrosis healing, we have employed whole genome microarray expression profiling as a discovery platform to identify genes. CCl4 and TAA liver fibrosis model mouse were used for this experiment. After five weeks liver fibrosis induction period, mouse have been observed for one week (1w) or two weeks (2w) and negative control nucleotide (N.C) or miR-29a were injected every 3 days on this period. We used CCl4 1w N.C (n = 1), 1w miR-29a (n = 1), 2w N.C (n = 1), 2w miR-29a (n = 1), and also used TAA model mouse (total n = 8) liver samples for microarray analysis. We can get only one gene (PDGF-c) as a target of miR-29a which relate to liver fibrosis and down-regulated more than 1.5 times in common miR-29a injected group than N.C group. CCl4 and TAA liver fibrosis model mouse were used for this experiment. After five weeks liver fibrosis induction period, mouse have been obserbed for one week (1w) or two weeks (2w) and negative control nucleotide (N.C) or miR-29a were injected every 3 days on this period. We used CCl4 1w N.C (n = 1), 1w miR-29a (n = 1), 2w N.C (n = 1), 2w miR-29a (n = 1), and also used TAA model mouse (total n = 8) liver samples for microarray analysis.
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