NEURONAL REPLACEMENT THERAPIES IN TWO ANIMAL MODELS OF BRAIN DAMAGE: TOWARDS THE SEARCH FOR PHARMACOS AGAIN (Q3145164)
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Project Q3145164 in Spain
| Language | Label | Description | Also known as |
|---|---|---|---|
| English | NEURONAL REPLACEMENT THERAPIES IN TWO ANIMAL MODELS OF BRAIN DAMAGE: TOWARDS THE SEARCH FOR PHARMACOS AGAIN |
Project Q3145164 in Spain |
Statements
87,120.0 Euro
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108,900.0 Euro
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80.0 percent
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1 January 2019
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31 December 2022
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UNIVERSIDAD DE CADIZ
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11028
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LA MUERTE NEURONAL CAUSADA POR LESIONES DE CUALQUIER ETIOLOGIA COMO PUEDEN SER TRAUMATICAS, ACCIDENTES CEREBROVASCULARES ISQUEMICOS, ENFERMEDADES NEURODEGENERATIVAS ETC. ES UN PROCESO IRREVERSIBLE Y TODAVIA SIN TRATAMIENTO EFICAZ. EL DESCUBRIMIENTO DE CELULAS MADRE NEURALES (NSC) EN EL CEREBRO ADULTO HA ABIERTO LA POSIBILIDAD DE DESARROLLO DE NUEVAS TERAPIAS EN MEDICINA REGENERATIVA BASADAS EN LA REPOSICION NEURONAL A PARTIR DE CELULAS MADRE NEURALES (NEUROGENESIS). EN CONDICIONES FISIOLOGICAS, EXISTE NEUROGENESIS A PARTIR DE NSC UNICAMENTE EN DOS ZONAS DEL CEREBRO ADULTO, EL HIPOCAMPO Y LA ZONA SUBVENTRICULAR, MIENTRAS QUE EN EL RESTO DEL CEREBRO ADULTO NO EXISTE NEUROGENESIS O ES ESCASA. CUANDO SE PRODUCE UNA LESION CEREBRAL, LAS NSC SON RECLUTADAS EN EL PERIMETRO DE LA LESION Y PUEDEN VERSE CELULAS CON CARACTERISTICAS DE PRECURSORES NEURALES (NPC) QUE PROLIFERAN. VARIOS LABORATORIOS HAN DESCRITO QUE LOS NPC EN LAS LESIONES FORMAN MUY POCAS NEURONAS NUEVAS, BIEN PORQUE TIENDEN A DIFERENCIARSE A CELULAS GLIALES, BIEN PORQUE LOS PRECURSORES NEURONALES NO SOBREVIVEN EN LAS LESIONES. EL PROBLEMA RESIDE EN QUE EXISTEN MOLECULAS SEÑALIZADORAS EN EL ENTORNO DE LA LESION QUE ACTIVAN VIAS DE SEÑALIZACION INTRACELULAR QUE IMPIDEN LA FORMACION DE NUEVAS NEURONAS. ASI, ESTABLECER QUE MOLECULAS Y VIAS DE SEÑALIZACION PROMUEVEN LA NEUROGENESIS Y TRATAR DE MODULAR SU ACTIVIDAD PUEDE CONTRIBUIR A REGENERAR EL SISTEMA NERVIOSO DAÑADO. NUESTRO LABORATORIO HA DEMOSTRADO RECIENTEMENTE QUE EN LESIONES MECANICAS DE LA CORTEZA CEREBRAL SE SOBRE EXPRESAN PROTEINAS DE LA VIA DE SEÑALIZACION GLIOGENICA ADAM17/TGFALFA/EGFR Y QUE LA INHIBICION DE LA SECRECION DE TGFALFA MEDIADA POR ADAM17 FAVORECE LA FORMACION MASIVA DE NEURONAS EN LESIONES CEREBRALES QUE PROVIENEN NO SOLO DE CELULAS MADRE QUE SE ACTIVAN EN LA LESION, SINO DE PROGENITORES QUE MIGRAN DESDE REGIONES NEUROGENICAS. LA SELECTIVIDAD DE ADAM17 POR TGFA U OTROS DE SUS SUSTRATOS ESTA MEDIADA POR FOSFORILACIONES EN LAS MOLECULAS DEL LIGANDO/SUSTRATO CATALIZADAS POR PROTEINAS DE LA FAMILIA DE LAS PROTEINAS KINASA DE TIPO C (PKC). EN NUESTRO GRUPO HEMOS ANALIZADO EL EFECTO NEUROGENICO DE VARIOS DITERPENOS QUE ACTIVAN ISOTIPOS DIFERENTES DE PKC SOBRE LA NEUROGENESIS EN EL CEREBRO ADULTO SANO Y LESIONADAO. LOS ACTIVADORES DE PKC CLASICAS EJERCEN UN EFECTO PROLIFERATIVO SOBRE LOS NPC Y FAVORECEN LA NEUROGENESIS EN NICHOS NEUROGENICOS, MIENTRAS QUE LOS ACTIVADORES DE PKC NOVELES FAVORECEN LA DIFERENCIACION A NEURONAS DE LOS NPC Y LA MIGRACION DE NEUROBLASTOS DESDE LA ZONA SUBVENTRICULAR HACIA UNA LESIO. POR ESTOS MOTIVOS PROPONEMOS UN PROYECTO DIRIGIDO A: I) ENTENDER LOS MECANISMOS DE ACCION DE LAS ISOENZIMAS CLASICAS Y NOVELES EN LAS DIFERENTES ETAPAS DE LA NEUROGENESIS ADULTA: PROLIFERACION, MIGRACION Y DIFERENCIACION Y SU INTERACCION CON ADAM17, II) ESTUDIAR LOS EFECTOS A LARGO PLAZO DE MODULADORES DE PKC SOBRE LA NEUROGENESIS, LA DIFERENCIACION A NEURONAS FUNCIONALES DE LOS NEUROBLASTOS Y LA INTEGRACION DE ESTAS NUEVAS NEURONAS EN CIRCUITOS PREEXISTENTES, Y III) ESTUDIAR LOS EFECTOS DE ACTIVADORES DE PKC CLASICAS, ADMINISTRADOS EN ETAPAS INICIALES DE APARICION DE LA PATOLOGIA SOBRE LA FUNCION COGNITIVA EN UN MODELO DE RATON DE ENFERMEDAD DE ALZHEIMER ESPORADICA (SAMP8). (Spanish)
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NEURONAL CELL DEATH IN THE CENTRAL NERVOUS SYSTEM CAUSED BY DIFFERENT TYPES OF INJURIES SUCH AS TRAUMATIC AND ISCHEMIC BRAIN INJURIES, EPILEPSY, NEURODEGENERATIVE DISORDERS, ETC. IS AN IRREVERSIBLE PROCESS, WHICH HAS NO EFFICIENT TREATMENT NOWADAYS. THE RECENT DISCOVERY OF ADULT NEURAL STEM CELLS (NSC) HAS REVEALED THE THERAPEUTIC POTENTIAL OF ADULT NEUROGENESIS IN THE DEVELOPMENT OF NEW REGENERATIVE THERAPIES FOR BRAIN INJURIES. PHYSIOLOGICALLY, GENERATION OF NEW NEURONS FROM NSC OCCURS MAINLY WITHIN TWO REGIONS OF THE ADULT BRAIN: THE DENTATE GYRUS OF THE HIPPOCAMPUS AND THE SUBVENTRICULAR ZONE, WHEREAS NEUROGENESIS IN OTHER BRAIN AREAS BARELY EXISTS. UPON BRAIN INJURY NSC ARE RECRUITED INTO THE DAMAGED AREA AND PROLIFERATIVE NEURAL PROGENITOR CELLS (NPC) CAN BE FOUND AROUND THE LESION. SEVERAL LABORATORIES HAVE PREVIOUSLY DESCRIBED THAT NPC IN LESIONS PROLIFERATE BUT HAVE A TENDENCY TO PRODUCE A VERY SMALL NUMBER OF NEURONS. THE MAIN DRAWBACK UNDERLYING THE INSUFFICIENT NEURONAL FORMATION IN DAMAGED BRAIN AREAS IS THE PRESENCE IN THE INJURED TISSUE OF SIGNALING MOLECULES RELEASED WITHIN THE PERI-LESIONAL AREA, WHICH ACT ON RECEPTORS COUPLED TO SIGNALING CASCADES THAT IMPAIR NEURONAL REPLACEMENT FAVORING GLIAL CELL FORMATION. BASED ON THESE PREMISES, STRATEGIES AIMED TO REGENERATE DAMAGED BRAIN REGIONS SHOULD BE BASED ON ESTABLISHING MOLECULES THAT PROMOTE NEUROGENESIS AND ON MODULATING THE ACTIVITY OF SUCH MOLECULES. OUR LABORATORY HAS RECENTLY DEMONSTRATED THAT MECHANICAL CORTICAL BRAIN LESIONS INDUCE THE EXPRESSION PROTEINS OF THE GLIOGENIC SIGNALING PATHWAY ADAM17/TGFALPHA/EGFR AND THAT INHIBITION OF TGFALPHA RELEASE PROMOTES MASSIVE NEURONAL FORMATION IN CORTICAL BRAIN LESIONS. NEURONS IN THESE LESIONS ARE NOT ONLY GENERATED BY STEM CELLS LOCALLY ACTIVATED AT THE SITE OF INJURY, BUT ALSO FROM MIGRATING NEUROBLASTS ORIGINATED IN THE SUBVENTRICULAR ZONE. SELECTIVITY OF ADAM17 FOR TGF OR OTHER SUBSTRATES IS MODULATED BY SUBSTRATE PHOSPHORYLATION REACTIONS CATALYZED BY PROTEINS OF PROTEIN KINASE C (PKC) FAMILY. OUR GROUP HAS ANALYZED THE NEUROGENIC EFFECT OF SEVERAL DITERPENES, WHICH ACTIVATE DIFFERENT PKC ISOTYPES FINDING THAT CLASSICAL PKC ACTIVATORS PROMOTE NPC PROLIFERATION, AND NEUROGENESIS IN NEUROGENIC NICHES SUCH AS THE HIPPOCAMPUS, WHEREAS NOVEL PKC ACTIVATORS FAVOR NEURONAL DIFFERENTIATION OF NPC IN INJURIES AND NEUROBLAST MIGRATION FROM THE SUBVENTRICULAR ZONE TOWARDS AN INJURY. THUS, IT IS REASONABLE TO HYPOTHESIZE THAT CLASSICAL PKC ACTIVATING DITERPENES MIGHT BE USEFUL TO AMELIORATE THE LOSS OF MEMORY IN EARLY STAGES OF A SENESCENCE MICE MODEL, IN WHICH HIPPOCAMPAL NEUROGENESIS NEEDS TO BE BOOSTED, WHEREAS NOVEL PKC ACTIVATORS MIGHT BE HELPFUL TO FACILITATE MIGRATION OF NEUROBLASTS TOWARDS A MECHANICAL BRAIN INJURY. BASED ON THESE FINDINGS, WE NOW AIM TO STEP FORWARD AND WE ARE PROPOSING A PROJECT DESIGNED TO: I) UNDERSTAND THE MECHANISMS OF ACTION OF CLASSICAL AND NOVEL PKC ISOZYMES ON ADULT NEUROGENESIS, PROLIFERATION, DIFFERENTIATION AND MIGRATION AND THEIR INTERACTION WITH ADAM17; II) STUDY THE LONG-TERM EFFECTS OF NOVEL PKC MODULATORS ON NEUROGENESIS IN BRAIN INJURIES, FUNCTIONAL DIFFERENTIATION OF NEUROBLASTS INTO FUNCTIONAL NEURONS AND THEIR INTEGRATION INTO PRE-EXISTING CIRCUITS AND III) STUDY THE EFFECTS OF CLASSICAL PKC ACTIVATORS ON COGNITIVE PERFORMANCE IN A MICE MODEL OF SPONTANEOUS ALZHEIMER¿S DISEASE (SAMP8) WHEN ADMINISTERED WHEN ADMINISTERED AT EARLY STAGES AT THE ONSET OF THE SYMPTOMS. (English)
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Puerto Real
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Identifiers
RTI2018-099908-B-C21
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