Kilpatrick/Burstyn-Cohen joint PhD projects

Prof Trevor Kilpatrick and Prof Tal Burstyn-Cohen

UoM Prof Trevor Kilpatrick: tkilpat@florey.edu.au

The Florey Department of Neuroscience and Mental Health, The University of Melbourne

The Florey Institute of Neuroscience and Mental Health

https://www.florey.edu.au/science-research/scientist-directory/professor-trevor-kilpatrick

UoM co-supervisor Michele Binder: michele.binder@florey.edu.au

The Florey Institute of Neuroscience and Mental Health

HUJI Prof Tal Burstyn-Cohen: talbu@ekmd.huji.ac.il

Institute for Dental Sciences Faculty of Dental Medicine, Hebrew University of Jerusalem

WWW.TBCLAB.COM

 

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

 

Project 1: Home base – UoM

Understanding PROS1-TAM Rs signalling in myelination and repair.

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

 

Project 2: Home base- HUJI

Deciphering the role of TAM receptors and ligands in the diseased / injured brain

Traumatic brain injury (TBI) is an acute insult to the brain, and a leading cause of death and disability in both civilian and military populations. TBI is characterized by neuronal and white matter loss, with resultant brain atrophy and functional neurological impairment. Beyond the immediate TBI injury and associated morbidity, the long-term negative outcomes are memory and cognitive impairment, motor disability, increase risk for Alzheimer’s and Parkinson’s diseases, all leading to a poor quality of life. Thus, improving recovery from TBI remains a major challenge in the clinic. The two main hurdles for recovery following damage to the nervous system are (1) the removal of dead dells and myelin debris by phagocytic cells and (2) restraining the deleterious outcomes of a strong inflammatory response to allow for neuroprotection. Therefore, tilting the balance towards neuroprotection and regeneration would support better outcome. This project will define the role of PROS1 and MERTK in overcoming both hurdles: enhancing debridement by MG and curbing inflammation at the same time. We hypothesise that PROS1 and MERTK, both highly expressed by human and mouse microglia will function to improve recovery following TBI. The HUJ group has established a TBI model to research the roles of PROS1 following TBI, utilizing the MG-Pros1-cKO mice. Preliminary data obtained by the HUJ group indicates PROS1 is an immediate responder after TBI. The TBI model will be established and the role of MERTK in TBI will be investigated at UoM, using MG-MERTK-cKO. Both groups will further investigate the mechanism by which PROS1 (HUJ) and MERTK (UoM) function ameliorates TBI outcome by reducing the negative effects of inflammation, and enhancing clearance of dead cells and degraded myelin both in-vitro and in-vivo. The importance of PROS1, MERTK and the mechanisms by which they function will be investigated at the cellular and molecular levels.

Year 1/2: HUJI – The HUJ student will initially undertake the investigation of the role of PROS1 in TBI at HUJ and learn the TBI model

Years 2/3: UoM – investigate the role of MERTK in transducing the PROS1 effects, including training in OL and myelin biology