PHAGOCYTOSIS

"Molecular Mechanisms underlying the link between the vitamin K-dependent proteins, Gas6 and protein-S, and phagocytosis of apoptotic cells during cell differentiation processes"

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 Obiettivo del progetto (Objective)

'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.'

Introduzione (Teaser)

Vitamin K-dependent proteins are mainly associated with blood coagulation disorders. They regulate cell self-destruction and the ability to engulf solid particles.

Descrizione progetto (Article)

Vitamin K-dependent proteins include the anticoagulants protein-S and Growth arrest-specific 6 (Gas6), which possess a similar structure and are produced in the liver, retina, brain and testes.

The EU-funded 'Molecular mechanisms underlying the link between the vitamin K-dependent proteins, Gas6 and protein-S, and phagocytosis of apoptotic cells during cell differentiation' (Phagocytosis) project is investigating the role of vitamin K in regulating the cell membrane's ability to envelop particles resulting from the breakdown of cells. The work will contribute to the development of new therapies for treating disorders associated with cell differentiation.

Researchers have developed a technique based on a culture of Sertoli cells, a highly specialised cell found in the testes. The cell culture was exposed to either tissue-specific substrates (from the testes) or a tissue non-specific substrate (from the retina) and analysed during phagocytosis. Defects in phagocytosis can result in problems during cell differentiation, the process by which a generic cell becomes more specialised.

Results have indicated that the nature of the substrate is an important factor that should be considered when studying the molecular mechanism behind phagocytosis. The research has helped to explain the role of the vitamin K-dependent factor protein-S in regulating phagocytosis in apoptotic cells. Apoptosis is the normal, programmed death of a cell in a living organism, after which new cells are regenerated.

The Phagocytosis initiative is giving scientists a clearer understanding of apoptotic substrate clearance in healthy and diseased states. This can help in the development of new therapies for targeting conditions associated with phagocytosis defects such as neurodegenerative disease, blindness and infertility. These are conditions that are becoming major health challenges in Europe as its population ages.