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Project List » Brain ageing under radiation: PINK1 role in DNA damage response following proton-induced neurodegeneration

Brain ageing under radiation: PINK1 role in DNA damage response following proton-induced neurodegeneration
www.nipne.ro/proiecte/pn3/21-projects.html


Acronym: BRAG
Contracting Authority: Executive Agency for Higher Education, Research, Development and Innovation Funding (UEFISCDI)
Number / Date of the contract: /
PN-III-P1-1.1-PD-2019-0862
Project Manager: Mihaela Temelie
Partners:
Starting date / finishing date: 2020-09-01 / 2022-08-31
Project value: 246950 RON
Abstract: With increased lifespan and technology use more and more people are affected by neurodegenerative disease. Neuronal loss is triggered by complex processes that involve genetic and environmental factors leading to accumulation of cellular disfunctions.
Age-related mechanisms were proved to be involved: mitochondrial dysfunction, accumulation of dysfunctional protein and persistent DNA damage. PINK1, a mitochondrial kinase has been found to be mutated in genetic familial Parkinson disease (PD) cases and his loss-of-functions models are widely used in neurodegeneraton studies.
However, only few very recent studies are focused on connection of mitochondrial pathways with DNA-damage response in neurodegeneration. We propose here to link mitochondrial dysfunction, DNA damage repair and neuroinflammation in order to understanding the early cellular events involved in neuronal loss.
The aim of our study is to reveal PINK1 interactions in DNA Damage Response (DDR) in a neurodegeneration model induced by proton radiation exposure. The mechanisms will be first studied on a simple cellular model (SH-SY5Y differentiated cells) and later on in the context of neuroinflammation. For this, we will characterize proton radiation as a modulator of glial activation and we will establish an in vitro co-culture model comprising neuronal and activated glial cells.
The project will lead to establish and characterize of the described model and identify of neuronal DDR pathways modulated by PINK1 in the context of neuronal microenvironment. On a longer time-scale the project can lead to reveal specific key proteins that can be used as target for development of new therapeutic strategies for brain ageing disease.

Objectives: We will be focused on understanding the early cellular events involved in neuronal loss that occur following radiation exposure, in ageing and neurodegenerative diseases. The aim of our study is to reveal PINK1 interactions in DNA Damage Response (DDR) following proton exposure.
The project will following objectives: Evaluation of PINK1 role in neuronal signalling pathways of DDR following proton radiation. Evaluation of proton radiation as a modulator of inflammatory response in glial cellular models. Establish and characterzation of a complex in vitro model of neurodegeneration comprising neuronal and glial cells in co-culture.

THE STAGES OF THE PROJECT AND DELIVERY DATES
1. Establish and validation of cellular models relevant for neurons and glial cells in inflammatory context  (2020-12-31)
2. PINK1 role in response to proton beam irradiation in SH-SY5Y cells and in a complex neurodegeneration model  (2021-12-31)
3. Evaluation of DNA repair mechanisms modulated by PINK1 in neuroinflammation models (2022-08-31)

RESULTS
PUBLISHED ARTICLES
RESEARCH TEAM


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