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| Status |
Public on Oct 06, 2022 |
| Title |
Blockade of the Protease ADAM17 Ameliorates Experimental Pancreatitis |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Acute and chronic pancreatitis, the latter associated with fibrosis, are multifactorial inflammatory disorders and leading causes of gastrointestinal disease-related hospitalisation, including death. Despite the global health burden of pancreatitis, currently there are no effective therapeutic agents. In this regard, the protease A Disintegrin And Metalloproteinase 17 (ADAM17) mediates inflammatory responses through shedding of bioactive inflammatory cytokines and mediators, including tumour necrosis factor α (TNFα) and the soluble interleukin (IL)-6 receptor (sIL-6R), the latter of which drives proinflammatory IL-6 trans-signalling. However, the role of ADAM17 in pancreatitis is unclear. To address this, Adam17ex/ex mice – which are homozygous for the hypomorphic Adam17ex allele resulting in marked reduction in ADAM17 expression – and their wild-type (WT) littermates were exposed to the cerulein-induced acute pancreatitis model, and acute (1-week) and chronic (20-weeks) pancreatitis models induced by the cigarette smoke carcinogen nicotine-derived nitrosamine ketone (NNK). Our data reveal that ADAM17 expression was upregulated in pancreatic tissues of animal models of pancreatitis. Moreover, the genetic (Adam17ex/ex mice) and therapeutic (ADAM17 prodomain inhibitor; A17pro) targeting of ADAM17 ameliorated experimental pancreatitis, which was associated with a reduction in the IL-6 trans-signalling/STAT3 axis. This led to reduced inflammatory cell infiltration, including T cells and neutrophils, as well as necrosis and fibrosis in the pancreas. Furthermore, upregulation of the ADAM17/IL-6 trans-signalling/STAT3 axis was a feature of pancreatitis patients. Collectively, our findings indicate that the ADAM17 protease plays a pivotal role in the pathogenesis of pancreatitis, which could pave the way for devising novel therapeutic options to be deployed against this disease.
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| Overall design |
RNA transcriptome sequencing to profile the differential regulation of gene networks in pancreatic tissues of WT and Adam17ex/ex mice subjected to cerulein-induced acute pancreatitis (AP) and compared to PBS controls.
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| Contributor(s) |
Saad MI, Gearing LJ, Jenkins BJ |
| Citation(s) |
36215509 |
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| Submission date |
Oct 03, 2022 |
| Last update date |
Jan 05, 2023 |
| Contact name |
Jamie Gearing |
| Organization name |
Hudson Institute of Medical Research
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| Street address |
27-31 Wright St
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| City |
Melbourne |
| ZIP/Postal code |
3168 |
| Country |
Australia |
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| Platforms (1) |
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| Samples (16)
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| GSM6614027 |
WT pancreas, PBS, replicate 4 |
| GSM6614028 |
WT pancreas, Cerulein, replicate 1 |
| GSM6614029 |
WT pancreas, Cerulein, replicate 2 |
| GSM6614030 |
WT pancreas, Cerulein, replicate 3 |
| GSM6614031 |
WT pancreas, Cerulein, replicate 4 |
| GSM6614032 |
Adam17 ex/ex pancreas, PBS, replicate 1 |
| GSM6614033 |
Adam17 ex/ex pancreas, PBS, replicate 2 |
| GSM6614034 |
Adam17 ex/ex pancreas, PBS, replicate 3 |
| GSM6614035 |
Adam17 ex/ex pancreas, PBS, replicate 4 |
| GSM6614036 |
Adam17 ex/ex pancreas, Cerulein, replicate 1 |
| GSM6614037 |
Adam17 ex/ex pancreas, Cerulein, replicate 2 |
| GSM6614038 |
Adam17 ex/ex pancreas, Cerulein, replicate 3 |
| GSM6614039 |
Adam17 ex/ex pancreas, Cerulein, replicate 4 |
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| Relations |
| BioProject |
PRJNA886653 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE214666_220311_Mohamed_ADAM17_umi_counts.csv.gz |
814.7 Kb |
(ftp)(http) |
CSV |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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