Task Particle Radiation-Induced Dysregulation of Protein Homeostasis in the Brain
Last Published:  04/20/22 11:43:24 AM (Central)
Short Title: Brain Protein Homeostasis
Responsible HRP Element: Space Radiation
Collaborating Org(s):
Funding Status: Active - Currently funded and in progress
Procurement Mechanism(s):
Solicited
Aims:
In this proposal, we plan to conduct in-depth investigations of those cellular pathways that regulate the removal of damaged proteins, repair of DNA damage, and response to conditions of oxidative stress through protein modifications in the brain. Protein modification by ubiquitin is a highly regulated process that is catalyzed by specific enzyme families that are capable of modifying the correct protein in the correct cellular location at the correct time in order to control important processes such as the maintenance of genomic stability, cell cycle progression, removal of damaged or misfolded proteins, impaired autophagy, apoptosis, and gene transcription. Depending on the radiation dose and beam quality, particle radiation may cause significant damage to proteins and oxidative stress in the cells in the central nervous system, leading to dysfunction of the cellular ubiquitin-related pathways, an increase in the levels of extracellular ubiquitin and persistent subsequent downstream effects on regulation of stress-associated signaling pathways in many different cell types within the CNS, precipitating neurodegenerative disease.

Aim 1: Quantitative assessment of particle-radiation induced cellular protein turnover to uncover alterations in pathway specific cellular ubiquitin pools and protein modification in vitro using cultured primary human and mouse neuronal stem cells.

Aim 2: Evaluate particle radiation induced alterations in protein ubiquitination in brain tissues of C57Bl6 -1 mice .

Aim 3: Evaluate particle radiation induced alterations in protein ubiquitination in brain tissues of a well-characterized and widely used triple transgenic 3xTg mouse model of Alzheimer's Diseases (AD).

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