0-TESTO COMPLETO.pdf - Fondazione Santa Lucia

Sezione III: Attività per progetti
DESCRIPTION OF THE RESEARCH PROJECT
Specific aims
Mutant SOD1 plays a causative role in motor neurons degeneration in
Amyotrophic Lateral Sclerosis (ALS). Increased oxidative stress and mitochondrial
damage are among the mechanisms whereby mutant SOD1 induces
neuronal death. Recently, a novel signaling mechanism involving the 66-kilodalton
isoform of the growth factor adapter Shc (p66Shc), that is operative in
the pathophysiological condition of oxidative stress, has been identified.
Given the pivotal role of p66Shc in the control of mitochondria-dependent
oxidative balance and energetic metabolism, and considering the lessened
susceptibility to oxidative stress and mitochondrial damage exhibited by mice
lacking p66Shc, we propose with this project to:
a) Investigate the role of p66Shc in mutSOD1-induced cell toxicity.
b) Attempt the rescue of correct mitochondria function in cellular models
for SOD1-linked familial ALS by genetic manipulation of the p66Shc-dependent
molecular pathway which underlies oxidative stress and mitochondrial
damage in cells.
To this aim, we will:
Aim 1 – Build and characterize cellular models of the disease that are
genetically modified for the activation or inhibition of p66Shc.
Aim 2 - Characterize the molecular mechanisms underlying p66Shcdependent
pathways which induce oxidative stress and mitochondrial damage
in cells.
Aim 3 – Assess the effects of p66Shc genetic manipulation on mitochondrial
metabolism of cells.
The achievement of this different objectives will allow to verify the importance
of mitochondrial redox signals by p66Shc in the regulation of ALS
pathogenesis, and is to be considered pivotal to future studies involving the
use of p66Shc -/- mice.
Novelty /Innovation
To our knowledge, no other group has ever tried to investigate on p66Shcmediated
pathways in ALS and there is no published literature on this subject.
Our preliminary data seem to be very promising and to encourage further
investigation. The proposed project is aimed to a better understanding of
this pathway in a cell model for SOD1-linked ALS, preliminary to experiments
in genetically modified mice.
BACKGROUND
Mitochondria are ‘the powerhouse of the cell’ because of their ability to
convert nutrients into ATP and they also play an essential role in intermediate
metabolism and in maintaining cellular Ca 2+ homeostasis. However, mito-
562 2009