The anti-coagulant factor protein-S and its structural homologue Gas6, two vitamin K-dependent proteins, are ligands for the Tyro3/Axl/Mer family of related tyrosine kinase receptors. Protein-S is the major factor responsible for serum-stimulated phagocytosis of apoptotic cells. The phenotypes associated with the invalidation of genes encoding Tyro3/Axl/Mer, further revealed the implication of protein-S and Gas6, in regulating apoptotic cell phagocytosis. We hypothesise that protein-S and Gas6 as well as other vitamin K-dependent proteins are major regulator of apoptotic cells phagocytosis, which is a critical step during cell differentiation. We intend to use Gas6-deficient mice, as well as RCS rats (deficient in Mer receptor) to investigate further the role of protein-S and Gas6 and possibly other vitamin K-dependent proteins in regulating cell differentiation and phagocytosis in three in vitro models of cell differentiation: retinogenesis, neurogenesis and spermatogenesis. The signalling pathways regulated by these factors and which are involved in mediating phagocytosis will also be investigated. The present research proposal also aims at setting up and standrising an in vitro quantitative assay for phagocytosis which will be a major technical advance and may form the framework for “phagosomics” as a new high-throughput screening assay to assess phagocytosis. Therefore, the present proposal may be of interest for also biotechnology companies. This research proposal will also contribute to establish possible links between the AVK anti-thrombotic treatment and retina degeneration, neurodegeneration, altered spermatogenesis/infertility. The link between blood coagulation factors and phagocytosis will be a new concept of major importance and will contribute to a better understanding a better assessment of its clinical consequences and to the development of cellular-based therapies aiming at an effective targeting of cell phagocytosis-associated pathologies.
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