0-TESTO COMPLETO.pdf - Fondazione Santa Lucia

Sezione III: Attività per progetti
Genetically modified mice that express the two human TNF receptors will be
generated by P13 to investigate the in vivo function of human specific therapeutics
targeting TNF receptors (month 24). In a complementary approach,
P14 will explore a recently identified mechanism of neuroprotection, which
involves the TNFR1 intracellular signaling pathway in CNS neurons and is
effective in acute excitotoxic and ischemic brain injury, and use this information
to develop cell penetrating compounds that will enhance this neuroprotective
pathway (month 24). The therapeutic efficacy of the above compounds
will be tested in in vitro systems, humanized animal models and other models
of neuroinflammation/neurodegeneration utilized by the consortium (up to
month 60).
c) To evaluate the efficacy of sodium channel blockers and calcium channel
blockers and glutamate receptor antagonists, in axonal protection. New
drugs that block different types of sodium channels, inhibit the reverse mode
of operation of the sodium/calcium exchanger and counteract the neurotoxic
actions of glutamate receptor activation leading to excessive accumulation of
cytosolic calcium will be tested by P24 (ex P11) and P18 (until month 24) in
experimental systems of increasing complexity (month 36). This should help
identify the best compound to be used in clinical trials (month 48 or 60).
d) To evaluate the therapeutic efficacy of combined anti-apoptotic and
anti-inflammatory compounds in a rat model of EAE with optic neuritis. Specific
intracellular pathways involved in neuronal apoptosis will be manipulated
by treatment with neurotrophic factors, neurotrophin-like substances,
pharmacological approaches or new protein transfer tools (TAT-fusion proteins)
developed by P2a (month 36). These tools will be also tested in combination
with known immunomodulatory agents and compounds developed by
other partners (up to month 60).
The generation of new compounds, tested for their anti-inflammatory and
neuroprotective efficacy, and of bifunctional molecules for targeting of neuroprotective
activities specifically to neurons and glial cells will permit the application
of innovative approaches for the treatment of neuroinflammatory diseases.
The simultaneous development and complementarity of the strategies
described above ensures that substantial interactions and synergism among
participants will take place during the entire project and will lead to new
insights into the mechanisms underlying inflammatory neurodegeneration
and neuroprotection, opening the way to the evaluation of combination therapies
in clinical trials.
To accelerate the achievement of the NeuroproMiSe objectives, horizontal
activities will be developed through the establishment of neuropathology and
genomics/proteomics facilities (month 1 or 7 to 60) and training activities
(month 10 to 60). This will ensure the uniform availability and distribution of
technological know-how in cutting-edge technologies of lesion analysis/imaging
and functional genomics.
The NeuroproMiSe management will be implemented through a General
Assembly and a Steering Committee, which will oversee all scientific, training,
innovation and administrative activities of the consortium (month 1 to 60). To
600 2009