Opis projektu
Kontrola metaboliczna wzrostu guza i epileptogeneza – przypadek glejaków
Glejaki mogą wykazywać mutacje w genie dehydrogenazy izocytrynianowej, co prowadzi do nadprodukcji onkometabolitu D-2-hydroksyglutaranu (D2HG). Uważa się, że D2HG bierze udział zarówno w procesach epileptogennych, jak i onkologicznych, modulując pobudzający neuroprzekaźnik, glutaminian. Celem finansowanego przez UE projektu GliomaSignals jest zbadanie roli D2HG w neurobiologii glejaków i wyjaśnienie mechanizmu, za pomocą którego moduluje on – wpływając na sygnalizację glutaminergiczną – wzrost guza i epizody padaczki. Badacze oczekują, że wyniki projektu rzucą światło na wysoką aktywność epileptyczną związaną z rozrostem glejaka i pozwolą odkryć nowe cele terapii.
Cel
Dysregulated growth processes of gliomas interact with pro-epileptic plasticity of brain circuits in such a way that the excitatory transmitter glutamate promotes autocrine tumor invasion as well as epileptic synchrony in surrounding cortical regions. Most low-grade gliomas are associated with mutations of Isocitrate DesHydrogenase (IDH) genes which lead to an excess of the oncometabolite D-2-Hydroxyglutarate (D2HG). With a structure mimicking glutamate, D2HG is thought to participate in both epileptogenic and oncologic processes. Importantly, while epileptic activity is accentuated, tumor prognosis is improved in affected people. My preliminary data now suggest a dual function for D2HG, acting as a glutamatergic agonist at high levels, but as an antagonist in the presence of glutamate. Solving this paradox will be a step forward in glioma science. The GliomasSignals project will examine the role of D2HG in the neurobiology of gliomas bringing electrophysiology concepts and tools to neuro-oncology, seeking to transform our understanding. It seeks to better understand how D2HG modulates glutamatergic signaling, affects neuronal excitability and tumor growth, and to detect the extent to which tumor infiltration colocalizes with epileptic remodeling. In vivo and in vitro work mostly on human tissue will aim at: 1- Map biomarkers of epileptic activity / tumor infiltration by cortical recordings during surgery using unique next generation Neurogrid electrodes. 2- Correlate D2HG levels, glutamate concentrations and tumor infiltration with recordings in peritumoral cortex at an unprecedented resolution. 3- Identify D2HG effects on glutamate signaling in human tissue slices producing epileptic activities and in a rodent model. 4- Explore D2HG long-term effects on epileptic activity and tumor growth / infiltration in co-cultures of tumors with surrounding peritumoral cortex by exploiting our unique capabilities for long-term human cortex organotypic cultures.
Dziedzina nauki
Słowa kluczowe
Program(-y)
Temat(-y)
System finansowania
ERC-COG - Consolidator GrantInstytucja przyjmująca
75654 Paris
Francja