0-TESTO COMPLETO.pdf - Fondazione Santa Lucia

RF07.74 – Development of new strategies against neuroinflammatory processes associated…
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What the project adds to the information already available
ALS involves degeneration of motor neurons, and its precise pathogenic
mechanism is not clear, but implicated in motor neuron dysfunction and
death are protein misfolding and aggregation, defective axonal transport,
mitochondrial dysfunction and excitotoxicity via faulty glutamate reuptake
into glial cells or abnormal RNA editing in GluR2 subunits of glutamate
receptors, producing increased Ca 2+ entry into neurons and contributing to
neuronal death. Besides to a similar cascade of toxic events occurring even
in HD, recent evidences of glial activation added relevance to the hypothesis
that inflammatory processes may contribute to neurodegeneration, by
releasing proinflammatory cytokines. Presently, no biological markers of
inflammation have been detected in HD, neither any relationship among
microglial activation, neuronal dysfunction and clinical ratings of the disease,
have so far been elucidated. This study is focused on excitotoxicity by
Glu and on neuroprotection studying specific neuronal factors such as glial
factors, including neurotransmitters, chemokines and ubiquitous factors,
such as the neuro-protector and anti-apoptotic factor Che-1. This represents
a new strategy in the study of the molecular mechanisms and the inflammatory
processes responsible for neurodegeneration events in HD and ALS and
may add new information useful to develop new therapeutic roads against
these pathologies.
OBJECTIVE(S)
The main goal of our project is to find new therapeutic strategies against
neurodegenerative pathologies associated with inflammation. To this purpose,
we aim to describe some of the molecular mechanisms leading from the interaction
between CNS cells and inflammatory mediators to the neurodegeration
observed in the HD and ALS patients, and in related animal models. Each PU
will contribute to the main objective by addressing a specific problem concerning
neuroinflammation and neurodegeneration.
P.U.1: In order to clarify the cross-talk between neurons and glia during
neuroinflammation, this Unit will analyse the role exerted by mGlu receptors
in the modulation of the expression and the activity of the inflammatory molecules
such as cytokines, chemokines and low-weight mediators (e.g. NO,
adenosine) produced by glial cells in different conditions. Microglial cultures
and CNS tissue slices from animal models of neurodegenerative pathologies
will be analysed to quantify the expression of inflammatory mediators and to
describe the modulation of the neuronal electrophysiological properties in the
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