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(MRC DTP) Insulin-mediated antimicrobial secretion from pancreatic acinar cells regulates the gut microbiome and barrier function: Link between diabetes and severity of acute pancreatitis


Project Description

Acute pancreatitis is a serious and sometimes fatal inflammatory disease of the pancreas. Severe cases are characterised by infected pancreatic necrosis, sepsis and multiple organ failure, which increases mortality and prolongs critical care occupancy.
There is strong clinical evidence linking diabetes (both type-1 and type-2) and the severity of pancreatitis. Moreover, ongoing and pilot studies show that caerulein-induced-pancreatitis is worse in type-1 diabetic mice (Ins2Akita) and Pancreatic Acinar Conditional Insulin Receptor Knock Out mice (PACIRKO), in which the insulin receptor is specifically deleted in acinar cells using a tamoxifen-inducible Cre-lox-based gene deletion system. This is due in part to insulin directly protecting pancreatic acinar cells from cellular injury by driving glycolytic metabolism, thereby preserving cellular ATP, preventing cytotoxic Ca2+ overload and preventing necrotic cell death.
However, additional pilot data show that the antimicrobial peptide (AMP), REG3β, is expressed abundantly and secreted from pancreatic acinar cells in response to insulin, which was abolished in PACIRKO mice that lack insulin receptors. Moreover, PACIRKO mice that lack IRs and REG3β secretion, also exhibited altered gut phenotype including inflammation (CD45), reduced mucus-secreting goblet cells (Alcian blue) and tight junction protein expression (occludin) within colonic enterocytes.
The over-arching aim of this project is to test the hypothesis that endogenous insulin regulates REG3β secretion from pancreatic acinar cells which maintains a healthy gut microbiome and gut barrier function. However, diabetes results in reduced REG3β secretion leading to gut dysbiosis, loss of barrier function and thus systemic bacteremia which increases the severity of pancreatitis. This will be directly and unambiguously tested by comparing the antimicrobial activity of the pancreatic acinar cell “secretome” and numerous aspects of gut phenotype in PACIRKO mice, which lack acinar IRs and REG3β secretion, vs littermate control mice (double floxed insulin receptor (IRlox/lox) mice). This includes gut dysbiosis (16S rRNA metagenomics), inflammation (anti-CD45-lebelled haematopoietic cells, anti-CD3-labelled T-cells), mucus secretion (Alcian blue, anti-MUC2, anti-MUC5AC, barrier function (anti-claudin-2, occludin, anti-ZO1) and bacterial translocation (plasma bacterial DNA and endotoxin).
The successful outcome of this project could provide strategies for correcting the impaired gut phenotype during diabetes, thereby potentially reducing the severity of acute pancreatitis.

Entry Requirements:
Applications are invited from UK/EU nationals only. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.

Funding Notes

This project is to be funded under the MRC Doctoral Training Partnership. If you are interested in this project, please make direct contact with the Principal Supervisor to arrange to discuss the project further as soon as possible. You MUST also submit an online application form - full details on how to apply can be found on the MRC DTP website View Website

As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.

References

1) Samad A, James A, Wong J, Mankad P, Whitehouse J, Patel W, Alves-Simoes M, Sirwardena AK & Bruce JIE. (2014) Insulin protects pancreatic acinar cells from palmitoleic acid-induce cellular injury. J Biol Chem. 289 (34) 23582-95
2) Mankad P, Siriwardena AK, Elliott AC, Bruce JIE (2012). Insulin protects rat pancreatic acinar cells from oxidant-induced inhibition of the plasma membrane calcium pump. J. Biol Chem. 287, 1823–36.
3) Ahuja M, Schwartz DM, Tandon M, Son A, Zeng M, Swaim W, et al. Orai1-Mediated Antimicrobial Secretion from Pancreatic Acini Shapes the Gut Microbiome and Regulates Gut Innate Immunity. Cell Metab. 2017;25(3):635-46.

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