Project name: Project category: Kind of research: Country: Principle investigator:

Cystic fibrosis and microparticle-mediated cellular cross talk within the pancreas: Impact of infection and immunosuppressive drugs on insulin secretion and pancreatic cell fate

Pathogenesis
France Florence Toti
Status: Ongoing
Abstract:

Microparticles (MPs) are plasma membrane fragments shed by cells submitted to metabolic, inflammatory or apoptotic stress. Released after plasma membrane remodeling, MPs are makers of the parental cell and of the stress that initiated their release. MPs behave as cellular effectors.
In cystic fibrosis infection by staphyloccocus aureus precedes that of Pseudomonas aeruginosa. Pancreatic degeneration first exocrine and later endocrine occurs as a progressive damage that leads to a specific form of diabetes in adulthood. Our team has established that exocrine CFTR∆F508 cells show exaggerated apoptosis in response to stress.
The final aim of the project is to determine the role of MPs shed from cells with CFTR deficiency in pancreas degeneration and the incidence of chronic infection in the loss of endocrine function occurring in the course of cystic fibrosis. Finally, to determine how immunosuppressive drugs might also alter MP effects in the pancreas of pulmonary transplanted patients with cystic fibrosis.
The role of CFTR∆F508 on the generation of deleterious MPs from exocrine pancreas that reduce insulin secretion by endocrine cells has been demonstrated last year and published using MPs produced in vitro after treatment by LPS from P aeruginosa . The role of leukocyte MPs and of specific bacterial virulence factors on pancreatic cells and their response to the stress generated by infection is currently under investigation
The project proposes to examine the incidence of immunosuppressive drugs on the properties of leucocyte and exocrine MPs towards endocrine cells and insulin secretion in the context of infection. MPs will be first produced in vitro by treatment of cells with LPS or PVL leucocidin. Effects of MPs and immunosuppressive drugs will be examined in cell lineages and in rat cultured islets. In vitro models will also allow the assessment of the properties of “natural” MPs isolated from patients with cystic fibrosis. The characteristic of MPs evidenced in vitro will be used to examine MP patterns in the plasma of mice bearing or not CFTR∆F508 mutation and infected by PVL leucocidin and LPS and in their pancreas.
The project, already initiated, is based on a collaborative work between 3 teams, expert in the field of MPcharacterization as cellular effectors and biomakers, islet pancreatic isolation and study , virulence factors andleucotoxins from staphylococcus aureus and pseudomonas aeruginosa in mice.

City: ILLKIRCH-GRAFFENSTADEN
Project amount (€): 20.000

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