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Characterization of the intracellular regulation of metalloproteases involved in brain plasticity

Until the 1970s it was believed that after a period of heightened plasticity in early life, the brain was no longer able to change, however, after that, research on brain plasticity has gained enormous interest.

Brain plasticity takes many forms: from the refinement of neural circuits during postnatal development into functional units essential for successful information processing, to the encoding of brief experiences into long-lasting memories in the adult brain. Plasticity processes occur at the levels of gene expression and proteins, neuronal structure and function as well as network dynamics are finely regulated.

In this project, we aim to investigate the intracellular role of metalloproteases (MMPs) involved in brain plasticity regulation. MMPs are proteases secreted by the cells that are important for several aspects of cell migration, from digestion of the extracellular matrix, to the activation of signaling molecules and regulation of ligand-receptor interactions as well as for increasing synaptic plasticity.

Differently from the “traditional” MMPs whose activation occurs in the extracellular space, the most recently identified family of MMPs, the ADAM-TS family are activated intracellularly. However, not much is known about the mechanism of ADAM-TSs intracellular regulation, trafficking and interactors. The working hypothesis is that the regulation of adult plasticity is due to local release of ADAM-TSs. Therefore, understanding the intracellular pathways leading to ADAM-TSs activation and secretion will allow to modulate their release and to test this hypothesis studying the effects on synaptic plasticity.

The student will conduct imaging studies on neuronal cell lines first and primary cells afterwards, by overexpressing fluorescent-tagged ADAM-TSs or by silencing using RNA interference to dissect their intracellular pathways and understand how the activity and the secretion of the ADAM-TS are regulated at cellular level.

Our research groups are part of the NorMIc Imaging Platform (http://www.mn.uio.no/ibv/english/research/about/infrastructure/imaging/) and CINPLA (www.cinpla.org). The findings will be used in computational models in collaboration with researchers at CINPLA and after having identified the molecular mechanisms regulating MMPs activation and secretion, the results can be used to modulate ADAM-TS activity in in vivo models for testing the effect on brain plasticity.

Publisert 22. mars 2018 10:28 - Sist endret 1. sep. 2021 15:24

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