student profile: Miss Calina Betlazar-maseh


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Thesis work

Thesis title: The impact of ionizing radiation on the central nervous system

Supervisors: Guo LIU , Richard BANATI

Thesis abstract:

Increased availability and utility of man-made sources of ionizing radiation, including that which is now widely used in medicine, has prompted greater focus into the biochemical and molecular mechanisms that are implicated after exposures to both high (>1 Gy) and low doses (<0.1 Gy). Whilst the biological responses to high dose ionizing radiation have been well characterized, there remains a striking lack of understanding and ambiguity over responses to low dose ionizing radiation, particularly in the highly complex central nervous system (CNS).

Orchestrating the innate immune responses to ionizing radiation in the CNS are the brain’s immune effector cells, microglia. These morphologically and functionally plastic cells respond to even subtle perturbations by transitioning to an activated phenotype. Exposure to high dose ionizing radiation results in increased expression and release of inflammatory signalling molecules and pro-inflammatory cytokines. At the subcellular level, ionizing radiation interacts with mitochondria to produce increased reactive oxygen species (ROS), which can also propagate the inflammatory/cytotoxic functions of activated microglia. In contrast, responses of microglia to low dose ionizing radiation have not been characterized, though other demonstrable CNS effects include upregulated antioxidant responses, indicative of possible neuroprotective effects. This thesis will therefore examine the potential differential modulation of microglial activation after high and low dose ionizing radiation exposure.

The almost exclusive upregulation of the mitochondrial translocator protein 18 kDa (TSPO) in activated microglia has facilitated in vivo characterisation of microglial activation in many pathological states of the CNS. Interestingly, the exact function of TSPO remains elusive. The recent generation of a TSPO knockout mouse model has revealed a putative role for TSPO in the mitochondrial energy network, with other evidence pointing towards an interaction with ROS, though this remains to be comprehensively understood. Due to the fundamental interaction between ionizing radiation and mitochondria, this thesis will explore TSPO as a potential biomarker of radiation-induced effects in the CNS. Concomitantly, this project will utilise ionizing radiation, a robust ROS-inducing stimulus, as an explorative means to gain insights into the putative functioning of TSPO in mitochondrial energetics and ROS formation.
The TSPO knockout mouse will be utilised to perform both in vitro and in vivo assays including immunohistochemistry, autoradiography and fluorescence/confocal microscopy to characterise the responses of microglia and TSPO expression after 0.01 Gy, 0.1 Gy and 2 Gy gamma irradiation. Together, this will ultimately enhance understanding of radiation-induced effects in terms of the innate immune response in the CNS.

Selected publications

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Journals

  • Betlazar-Maseh, C., Harrison Brown, M., Middleton, R., Banati, R., Liu, G. (2018). Cellular sources and regional variations in the expression of the neuroinflammatory marker translocator protein (TSPO) in the normal brain. International Journal of Molecular Sciences, 19(9), 1-18. [More Information]

2018

  • Betlazar-Maseh, C., Harrison Brown, M., Middleton, R., Banati, R., Liu, G. (2018). Cellular sources and regional variations in the expression of the neuroinflammatory marker translocator protein (TSPO) in the normal brain. International Journal of Molecular Sciences, 19(9), 1-18. [More Information]

Note: This profile is for a student at the University of Sydney. Views presented here are not necessarily those of the University.