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The role of mTOR-Brg1 interaction in normal and aberrant neuronal activity

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Project number:

2020/38/A/NZ3/00447

Title:

The role of mTOR-Brg1 interaction in normal and aberrant neuronal activity   

Project leader:

Jacek Jaworski, PhD, Professor
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Total budget:

4 092 140 PLN

Duration:

01.04.2021 -23.03.2026

About the project:             

In recent years, more and more attention is being paid to the links between the metabolism of nerve cells and their ability to respond to stimuli reaching them. One of the basic regulators of metabolism is mTOR protein. On the one hand, it senses the state of the cell's resources and on the other hand it is a sensor of extracellular stimuli, including neuronal activity. The integration of these two information ultimately determines the ability of the cell to respond to a given stimulus and adapt its metabolism to new conditions. Mutations in the mTOR regulating   genes lead   to   multi-organ   diseases   with   serious   neurological   and neuropsychological  symptoms.  One  of  such  diseases  is  tuberous  sclerosis  complex  characterized  by  the occurrence of epilepsy, mental retardation and autism spectrum disorders.

mTOR acts on many proteins changing their function, but occurs mainly in cytoplasm. However, the results of our previous research and the preliminary data which form the basis of this research proposal indicate that neuronal activity causes mTOR to move to the nucleus of the cell, where it interacts with proteins that modify the spatial packing of DNA. On this basis, we hypothesize that under favourable conditions of sufficient cellular resources (e.g., energy), neuronal activity causes mTOR to move to the nucleus, where it regulates the cellular functions of chromatin-modelling complexes, including expression of genes important for neuronal activity. At  the  same  time,  we  hypothesize  that  this  sequence  of  events  is  disturbed  in  tuberous  sclerosis  complex leading to changednerve cell activity, which causes epilepsy as well as disturbances in social interactions characteristic of autism spectrum diseases. The aim of the project is to verify this hypothesis using advanced molecular, cellular biology and microscopy methods. The research will use in vitro cultured neurons and Danio rerio. The results will contribute to a better understanding of the role of mTOR in physiology and brain  diseases. At  the  same  time  they  can  be  an  inspiration  for  scientists  working  on  other  mTOR-related diseases such as cancer and metabolic diseases.

The project is carried out as the MAESTRO grant of the Polish National Science Centre.