0-TESTO COMPLETO.pdf - Fondazione Santa Lucia

EC.11 – Neuroprotective strategies for multiple sclerosis
b) Humanized animal models will be generated to study the role in MSlike
disease evolution of autoreactive human CD8+ T cells recognizing an
HLA: neural self peptide complex relevant for MS or cross-reactive with
microbial antigens, and of epistatic interactions in the MS-associated DR2
haplotype (P4) (month 24).
c) The pathogenic relevance of ectopic lymphoid tissue (B-cell follicles)
in neuroinflammatory processes will be investigated by P1 in the MS brain
and in EAE models using strategies to promote or prevent the formation of an
intracerebral lymphoid microenvironment (month 24).
d) In vitro and in vivo models will be developed by P19 to study the signaling
pathways underlying axonal transport disturbance and axonal injury
induced by microglia-derived inflammatory mediators (month 24).
e) Characterization of the antigenic specificity of CD8+ T cells infiltrating
the MS brain (P7b).
f) Characterization of the EBV-specific CD8 T-cell response in MS
patients (P26).
The above studies are expected to generate new knowledge on MS
immunopathogenesis (month 36), which will help to define new rational ways
of developing disease modifying drugs, and new animal models useful for
analyzing interactions with newly identified genes and for evaluating the therapeutic
efficacy of neuroprotective compounds developed by other participants
(up to month 60).
3 – The third objective of NeuroproMiSe is to develop new neuroprotective
drugs based on targets identified and validated in animal models. As a
first step, a number of critical pathways of neurodegeneration and neuroprotection
will be investigated, and already existing and newly developed drugs
will be tested, in search of the best strategy to protect CNS cells from inflammatory
insults. Targets identified in the genetic and genomic studies and validated
in the disease models described above will also provide seeds for the
development of new therapeutic compounds. In this context, the specific tasks
will be:
a) To achieve neuroprotection by targeting molecules that are critically
involved in the regulation and function of myeloid cells, like the TREM-2
receptor and its associated signaling molecule DAP-12, and Ncf-1, a component
of the NAPDH oxidase complex. New compounds targeting the Ncf-1
pathway will be developed by P21 (previously P17), and starting from month
25 by P23 (replacing P21) (month 36). The molecular pathways regulated by
TREM-2 and Ncf-1 will be further explored (up to month 48). Moreover, compounds
modulating TREM-2 and Ncf-1 pathways will be evaluated for their
therapeutic efficacy in animal models of CNS inflammation (up to month 60).
b) To develop compounds targeting tumor necrosis factor receptor
(TNFR) subtypes for neuroprotective therapy (month 24). Based on previous
technology developed by the applicants (P12, P13, P16 and P22), genetic engineering
of human TNF and antibody-based reagents will be used to construct
novel TNFR specific agonists and antagonists capable of a selective triggering
of TNFR2 and a selective inhibition of TNFR1, respectively (month 24).
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