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Graduate student

Familial Mediterranean Fever  (FMF)

What is the role of the FMF protein (Marenostrin/Pyrin, M/P) in chemotaxis?

           
Summary
Familial Mediterranean fever (FMF) is the prototype of hereditary recurrent fever. Almost exclusively affecting populations of Mediterranean origin (Arabs, Armenians, Jews and Turks), this auto-inflammatory syndrome is characterized by recurring attacks of fever accompanied by serositis. The most severe complication in untreated patients is renal amyloidosis. The daily administration of colchicine not only abolishes acute crises but can also delay or reduce the occurrence of such renal complications. Unfortunately, the mechanism behind this effect remains unknown and between 5 and 10 % of patients do not respond to colchicine treatment.
The MEFV gene, responsible for the disease, is predominantly expressed in neutrophils and monocytes which are the mainly cells implicated in inflammatory response in innate immunity and encodes the Marenostrin/Pyrin (M/P) protein. Based on the dramatic inflammatory manifestations of FMF, P/M appears to be a major regulator of inflammation and innate immunity but its function remains uncertain and subject to controversy. Recently, we have identified several alternatively spliced MEFV transcripts in leukocytes and have highlighted various protein variants. We propose that these P/M variants could have different functions (pro- and anti-inflammatory) depending on the cell (neutrophiles and monocytes) and the inflammatory state.
The first aim of this thesis project will be to characterize the M/P variants identified by using siRNA and antibodies directed against the different variants. Their expressions depending on pro- and anti-inflammatory inducers will be analyzed and compared to those observed in leukocytes from FMF patients.
In a second aspect we will select one of the identified variants and we will define its role in chemotaxis and in the resolution of inflammation. Indeed, one of the main characteristics of the inflammatory attacks in FMF patients is the massive influx of neutrophils into the affected tissues and an increasing of neutrophiles chemotaxis at the inflammatory sites. Moreover, apoptosis and phagocytosis, the two mainly step of inflammation resolution is deregulated in FMF monocytes. The steps of inflammation will be analyzed and quantified by flow cytometry and microscopy in two hematopoietic cell lines as model. We will identify which step of inflammation is affected by M/P siRNA. The effects of the colchicine will be assessed at each step.

For more details please contact: Isabelle Touitou or Sylvie Grandemange

Postdoctoral fellowships

Any application are welcome, please contact us: Isabelle Touitou