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Joint PhD with HUJI: Understanding PROS1-TAM Rs signalling in myelination and repair

Project Description

TAM Receptors and their ligands: Deciphering multiple roles In CNS development, homeostasis and Injury for TYRO3 in developmental myelination and in myelin repair [2,7], the UoM group have recently established a role for MERTK-expressing MG in promoting normal myelination in the CNS, potentially by influencing the phagocytic capacity of these MGs. Moreover, current work from the HUJ group has revealed that PROS1 also influences microglial cell development and function. These data identify that the TAM-Rs MERTK and TYRO3 drive myelination in a cell type-specific manner, an effect potentially driven by MG-derived PROS1. This project, by combining the skills and resources of the two PIs, would specifically test the hypothesis that microglial-derived PROS1 promotes myelination via TYRO3 on OLs, neurons or both as well as via MERTK on MG. This project will test this hypothesis utilizing the unique tools available in the laboratories of the PIs; specifically mice deficient for PROS1 in MG (MG-Pros1-cKO) at HUJ, as well as mice deficient for MERTK in MG (MG-MERTK-cKO), mice deficient for TYRO3 in OLs (OL-Tyro3-cKO) or neurons (Neu-Tyro3-cKO) at UoM. The role of the PROS1-TAM-Rs axis in myelination will be investigated using cutting-edge techniques available in the UoM and HUJI laboratories including electron microscopic (EM) assessment of myelin ultrastructure, purification of relevant cell types (immunopanning) assessment of cell phenotype (in vitro myelination and phagocytosis), induction of myelin damage (cuprizone toxicity, experimental autoimmune encephalomyelitis). Key outcomes from this project include defining the importance of MGderived PROS1 in the establishment of normal myelination and in recovery from myelin damage, as well as delineation of the specific receptors and cell types upon which PROS1 exerts its effects.

Years 1 & 2: UoM – learn OL biology and relevant experimental techniques, in particular EM, immunopanning, in vitro myelination and in vitro phagocytosis assays, as well as induction of demyelination

Year 3 HUJI – utilise these techniques to investigate the importance of PROS1 in driving these effects in the HUJI laboratory

For interested candidates, although not required, a background in neurobiology, developmental biology, biology of inflammation, would be beneficial.

Funding Notes

This PhD is a part of an international research training group between the University of Melbourne (UoM) and the Hebrew University of Jerusalem (HUJI).The successful candidate will spend at least a year at each institution over the course of their candidature and be eligible to graduate with a jointly awarded PhD recognised with a testamur from each University.

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