0-TESTO COMPLETO.pdf - Fondazione Santa Lucia

Sezione III: Attività per progetti
quent maligant brain tumors in children that arise from the transformed precursors
of cerebellar granule cells. Understanding the transcellular and intracellular
pathways that regulate the biology of tumor stem cells is essential for
the identification and characterization of new molecular targets for the treatment
of brain tumors.
The project has the following primary objectives: (1) validation of mGlu3
metabotropic glutamate receptors as a potential target for the treatment of
malignant gliomas; (2) development of an in vitro assay useful for the screening
of drugs that promote the differentiation of glioma stem cell; (3) identification
of guanosine receptors and characterization of their role in the pathophysiology
or malignant gliomas; (4) identification of new diagnostic and
prognostic markers of malignant brain tumors; (5) identification of the role
played by muscarinic receptors in the biology of glioma cells. Patent of the
use of cholinergic drugs in the treatment of brain gliomas; (6) patent of Numb
as a drug target in the experimental treatment of medulloblastomas.
To reach these primary objective the project will; a) isolate and characterize
putative stem cells from human malignant gliomas; b) characterize how a
continous treatment with mGlu3 receptor ligands influences tumor growth in
nude mice after glioma cell or glioma stem cell xenografts in the brain
parenchima; c) characterize how treatment with mGlu3 receptor ligands or
genetic deletion of mGlu3 receptors influences brain tumor growth in mice
exposed to DNA alkylating agents during prenatal life; d) characterize how
activation or blackade of mGlu3 receptors influences differentiation of glioma
stem cells in vitro; e) characterize the signaling pathway(s) mediating the influence
of mGlu3 receptors on glioma stem cell differentiation focusing on the
interaction with bone morphogenetic proteins; f) isolate and separate glioma
stem cells expressing the glutamate transporter, GLAST; g) characterize how
expression of GLAST affects the biology of glioma stem cells in vitro and their
tumorigenesis in vivo; h) characterize how expression of GLAST influences
intracellular and extracellular glutamate levels and how activation of mGlu3
receptors regulate the expression of GLAST; i) characterize the expression and
function of muscarinic cholinergic receptors in glioma stem cells; j) characterize
how activation of muscarinic receptors regulates the expression of the
immediate early gene in glioma stem cells; k) select glioma cell lines responsive
to guanine based purines (GBPs); l) search for a novel guanosine receptors
mediating the action of GBPs in glioma cells; m) characterize the expression of
the novel guanosine receptor in human brain tissues and in specimens of
malignant gliomas; n) characterize how Y380 phosphorylation of caspase-8
influences the death and survival of glioma and neuroblastoma cells; o) characterize
how expression of pY380-caspase-8 and its phosphorylating enzyme,
Src, correlates with the clinical features of gliomas and neuroblastomas; p)
characterize how Numb regulates the activity of the Sonic Hedgehog pathway
and regulates cell proliferation in medullablastoma stem cells; q) generate
transgenic mice in which expression of Numb is under the control of a tetracicline-responsive
promoter and double mutant mice obtained by intercrossing
nestin-tetracycline responsive element-Numb mice with Patched-1+/- mice,
which are know to develop medulloblastomas when irradiated at PND1.
756 2009