Exposures to stress stimuli accumulating over the lifetime and combined with an inborn genetic susceptibility are essential to the development of age-related mitochondrial dysfunction and subsequent neurodegeneration.
This project is aimed at the identification of new potential therapeutic targets and agents among a range of prosurvival and neuroprotective compounds, such as humanin (HN) peptides, L-arginine (L-arg) and metabolic substrates, endowed with the ability to modulate and preserve mitochondrial energetic functions.
Mitochondrial dysfunction is key to cerebral injury. Ca+2 released by mitochondria leads to the activation of calcineurin, release of cytochrome c, generation of reactive oxygen species (ROS) generation, and induction of apoptosis. Aging is associated with accumulation of predominantly large, defective mitochondria, which do not produce ATP, but replicate mtDNA, generate ROS and resist autophagy. Cell survival and sustained mitochondrial function is modulated by a complex interplay of mechanisms, involving inflammatory factors.
Four well recognized university research groups established a Polish-Norwegian consortium to investigate mitochondrial biogenesis and functions in the search of protective mechanisms against the impairment of the vital processes of the brain. They study the metabolic (mitochodria-related) antiapoptotic mechanisms and neuroprotective effects of different endogenously formed peptides such as humanins and other bioactive compounds, including L-arg, and fatty acids, against proinflammatory, proapoptotic, hypoxic, and metabolic stressors in the brain cells (neurons, glia, endothelium), as well as in animal models (the NF-kappa B luciferase, and/or HIF-1 alpha luciferase, and transgenic mice overexpressing human TNFalpha models). They use the state-of-the-art technology available in the field, including transcriptomics, proteomics, metabolomics (tracing the radiolabeled metabolic compounds, LC/MS, GC/MS, HPLC, Bioplex system), analysis of the mitochondrial function (oxygraph high-resolution respirometry), cellular and tissue in vivo imaging and metabolic monitoring (in vivo confocal microscopy, flow cytometry), as well as different transgenic animal models (including the transgenic reporter luciferase mice).
The expected benefits of the project will include identification of novel biomarkers and the new therapeutic targets and improved strategies for prevention of neurodegeneration and dementia. It will also enhance, stimulate, and integrate scientific collaboration and help optimize the use of resources, and training of the new generation of young researchers.