Progetto: Investigation of mitochondrial function and novel therapies in Friedreich’s ataxia mouse models

Principal Investigator: Dr. Paola Giunti, Co-PI Andrey Abramov Department of Molecular Neuroscience Institute of Neurology, UCL, London

We propose to study the mitochondrial pathophysiology in FRDA using mouse models (YG8R and KIKO), and the pharmacological effects of Nrf2 inducers and D-PUFAs compounds on the mitochondrial function in  models, looking at different cell types variably involved in the disease, such as neurons and glia of the cerebellum and kidney fibroblast cells.

The methodologies chosen to achieve our goals include: cell biology, functional microscopy, fluorescence imaging techniques, and oxygen consumption measurements. Experiments will be conducted initially on primary cultures of cerebellar granular cells, co-cultures of neurons and glia, freshly isolated a kidney fibroblast cells. These cell culture preparations are currently used in our lab for other projects. The assays will include pre-clinical studies of two different types of drugs that will tackle potential therapeutic targets to envisage novel pharmaceutical trials for FRDA patients. The first type of compounds are Nrf2 inducers, that will trigger the antioxidant pathway of Nrf2, which has been found to be involved in FRDA (Shan et al,. 2013), and will also provide mitochondrial respiration substrates, helping the mitochondrial bioenergetics (Homstrom et al., 2013; Luthmann et al., 2013). The second type of compounds, D-PUFAs, will protect the cells from lipid peroxidation, which is relevant in FRDA mitochondrial function and, more importantly, our preliminary data has shown that FRDA mouse model cerebellar granule cells undergo dramatic increases in lipid peroxidation.

Finanziamento:133,000$ ( 1anno da 1 Maggio 2014) Co-finanziato da FARA