ROLE OF P73 AS A POSSIBLE REGULATOR OF REELIN IN COGNITIVE FUNCTION DURING AGING AND ALZHEIMER’S PATHOLOGY. IMPLICATION OF MICRODOMAINS LIPID RAFT. (Q3149247): Difference between revisions
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Revision as of 11:02, 9 October 2021
Project Q3149247 in Spain
| Language | Label | Description | Also known as |
|---|---|---|---|
| English | ROLE OF P73 AS A POSSIBLE REGULATOR OF REELIN IN COGNITIVE FUNCTION DURING AGING AND ALZHEIMER’S PATHOLOGY. IMPLICATION OF MICRODOMAINS LIPID RAFT. |
Project Q3149247 in Spain |
Statements
164,560.0 Euro
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193,600.0 Euro
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85.0 percent
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1 January 2018
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31 December 2020
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UNIVERSIDAD DE LA LAGUNA
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28°29'8.77"N, 16°18'57.38"W
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38023
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EL ENVEJECIMIENTO POBLACIONAL Y LA PATOLOGIA TIPO ALZHEIMER (EA, LA DEMENCIA DE MAYOR INCIDENCIA EN LA POBLACION DE EDAD AVANZADA) CONSTITUYEN UNA DE LAS PRIORIDADES EN LOS RETOS EN SALUD DE LA UNION EUROPEA. ELUCIDAR LOS DESENCADENANTES DE PROCESOS DE ENVEJECIMIENTO CEREBRAL ES DE GRAN IMPORTANCIA PARA EFECTUAR INTERVENCIONES PREVENTIVAS Y PALIATIVAS QUE CONTRIBUYAN A LA CALIDAD DE VIDA EN LA TERCERA EDAD. _x000D_ EN ESTE PROYECTO, INVESTIGAREMOS P73 (FACTOR DE TRANSCRIPCION PREPONDERANTE EN LA REGULACION DE LA MUERTE NEURONAL) EN LA MODULACION DE LA PROTEINA REELIN. REELIN ES DE IMPORTANCIA CRUCIAL EN LA PLASTICIDAD SINAPTICA, LAS FUNCIONES COGNITIVAS Y LA SUPERVIVENCIA NEURONAL, DURANTE EL DESARROLLO Y EN EL CEREBRO ADULTO. RECIENTEMENTE, SE HA DEMOSTRADO UN PAPEL DE ESTA PROTEINA EN NEUROPROTECCION FRENTE A EA AUN POR ELUCIDAR, QUE SERA INVESTIGADO EN ESTE PROYECTO._x000D_ UTILIZANDO UN MODELO KNOCK-OUT DE RATON PARA P73, HEMOS OBSERVADO ANTERIORMENTE QUE ESTOS RATONES PRESENTAN DEGENERACION CEREBRAL AGUDA MIENTRAS QUE, PARADOJICAMENTE, SON EXTREMADAMENTE LONGEVOS. ESTOS DATOS SUGIEREN UNA DUALIDAD DE P73 EN LA MUERTE CELULAR, SI BIEN SE DESCONOCEN LOS MECANISMOS MOLECULARES IMPLICADOS EN ESTE FENOMENO, QUE NOS PROPONEMOS CARACTERIZAR. _x000D_ POR OTRA PARTE, HEMOS DEMOSTRADO PREVIAMENTE QUE ALTERACIONES LIPIDICAS DE MICRODOMINIOS DE MEMBRANA NEURONAL LIPID RAFT SE MODIFICAN DURANTE EL ENVEJECIMIENTO NEURONAL, Y SON DESENCADENANTES DE PROCESOS NEUROPATOLOGICOS DESDE FASES ASINTOMATICAS DE EA. NUESTRAS OBSERVACIONES PRELIMINARES INDICAN QUE P73 SE UBICA EN LIPID RAFTS, Y PODRIA TENER UN PAPEL IMPORTANTE EN LA HOMEOSTASIS DE LOS MISMOS, AUN POR DEMOSTRAR._x000D_ EN ESTE PROYECTO, INVESTIGAREMOS LA POSIBLE MODULACION DE FACTORES DE SUPERVIVENCIA NEURONAL Y DE EVENTOS MOLECULARES TEMPRANOS DURANTE EL ENVEJECIMIENTO CEREBRAL Y EN PROCESOS DE DESARROLLO DE EA ASOCIADOS A LA REGULACION DE P73, Y LA IMPLICACION DE ALTERACIONES EN LA HOMEOSTASIS DE LOS LIPID RAFT. UTILIZAREMOS MUESTRAS DE CEREBRO HUMANO, MODELOS MURINOS KOP73, DE ENVEJECIMIENTO ACELERADO Y DE PATOLOGIA TIPO EA, CULTIVOS NEURONALES, Y MUESTRAS DE LIQUIDO CEFALORRAQUIDEO PROCEDENTES DE PACIENTES CON EA EN DIFERENTES ESTADIOS. _x000D_ MEDIANTE DIVERSAS APROXIMACIONES MORFOLOGICAS, BIOQUIMICAS Y METABOLICAS PRETENDEMOS: A) CARACTERIZAR LOS MECANISMOS POTENCIALES DE REGULACION DE P73 EN PROTEINAS RELEVANTES PARA LA SUPERVIVENCIA NEURONAL, REELIN Y KLOTHO, RECEPTORES NEUROTROFICOS DEL FACTOR DE CRECIMIENTO INSULINOTROPICO Y DE LOS ESTROGENOS, IGF-1R Y ER;, Y SU RELACION CON PROCESOS NEURODEGENERATIVOS EN ALZHEIMER; B) ELUCIDAR LA POSIBLE INFLUENCIA DE ALTERACIONES DE LOS LIPID RAFT EN LA ACTIVIDAD DE ESTAS PROTEINAS DURANTE EL ENVEJECIMIENTO NEURONAL; C) IDENTIFICAR LOS EVENTOS MOLECULARES Y METABOLICOS EN LIPID RAFTS ASOCIADOS CON LOS MARCADORES PROTEICOS DEL ESTUDIO, EN MUESTRAS DE LIQUIDO CEFALORRAQUIDEO Y EXOSOMAS EXTRAIDOS DE PACIENTES EN DIFERENTES FASES DE ALZHEIMER. _x000D_ LOS ABORDAJES PROPUESTOS PERMITIRAN CARACTERIZAR ASPECTOS RELEVANTES DEL ENVEJECIMIENTO CEREBRAL Y NEUROPATOLOGIAS ASOCIADAS, Y PROPORCIONARAN HERRAMIENTAS INNOVADORAS EN EL DIAGNOSTICO PRECOZ. ADEMAS, SE ESPERA QUE LOS RESULTADOS NOS PERMITAN COMPRENDER LOS CAMBIOS MOLECULARES Y CELULARES EN LAS CELULAS NERVIOSAS ASOCIADOS AL ENVEJECIMIENTO, COMO DETONANTES DE PROCESOS NEURODEGENERATIVOS. (Spanish)
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POPULATION AGEING AND PATHOLOGIES SUCH AS ALZHEIMER (AD, THE DEMENTIA WITH THE HIGHEST INCIDENCE IN AGED PEOPLE) CONSTITUTE ONE OF THE PRIORITIES IN HEALTH CHALLENGES IN THE EUROPEAN UNION. IT IS OF GREAT IMPORTANCE TO ELUCIDATE THE EVENTS TRIGGERING BRAIN AGEING TO ULTIMATELY ELABORATE PROCEEDINGS THAT MAY CONTRIBUTE TO THE QUALITY OF LIFE IN THE ELDERLIES. _x000D_ IN THIS PROJECT, WE WILL INVESTIGATE P73 (A TRANSCRIPTION FACTOR THAT PLAYS A PRIMORDIAL ROLE IN NEURONAL DEATH) IN THE MODULATION OF REELIN. REELIN IS OF CRUCIAL IMPORTANCE IN THE SYNAPTIC PLASTICITY, COGNITIVE FUNCTIONS, AND NEURONAL SURVIVAL DURING, BOTH, DEVELOPMENT AND ADULT BRAIN. RECENTLY, IT HAS BEEN DEMONSTRATED A ROLE OF REELIN IN NEUROPROTECTION AGAINST AD THAT STILL REMAINS TO BE ELUCIDATED. THIS ASPECT WILL BE INVESTIGATED IN THIS PROJECT._x000D_ USING A P73 KNOCK-OUT MURINE MODEL, WE HAVE PREVIOUSLY OBSERVED THAT THESE MICE SHOW ACUTE BRAIN DEGENERATION WHEREAS, PARADOXICALLY, THESE MICE ARE EXTREMELY LONG-LIVED. THESE DATA DEMONSTRATE A DUALITY OF P73 IN CELL DEATH, ALTHOUGH IT IS UNKNOWN THE MECHANISMS INVOLVED IN THIS PHENOMENON, THAT WE PROPOSE TO CHARACTERIZE HERE._x000D_ MOREOVER, WE HAVE PREVIOUSLY DEMONSTRATED THAT LIPID ALTERATIONS IN NEURONAL MEMBRANE MICRODOMAINS NAMED LIPID RAFTS ARE MODIFIED DURING NORMAL NEURONAL AGEING. THESE ALTERATIONS TRIGGER SOME NEUROPATHOLOGICAL PROCESSES SINCE ASYMPTOMATIC STAGES OF AD. OUR PRELIMINARY OBSERVATIONS INDICATE THAT P73 IS LOCATED IN LIPID RAFTS, WHERE IT MAY HAVE AN IMPORTANT ROLE IN RAFT HOMEOSTASIS, STILL TO BE INVESTIGATED._x000D_ IN THE PRESENT PROJECT, WE WILL INVESTIGATE THE POTENTIAL MODULATION OF NEURONAL SURVIVAL FACTORS, AND THE EARLY MOLECULAR EVENTS DURING NORMAL BRAIN AGEING, AND IN THE DEVELOPMENT OF PATHOLOGICAL AD PROCESSES ASSOCIATED WITH THE REGULATION OF P73, AS WELL AS THE INVOLVEMENT OF ABERRANT ANOMALIES IN THE HOMEOSTASIS OF LIPID RAFTS. FOR THIS STUDY, WE WILL USE HUMAN BRAIN SAMPLES, MURINE MODELS KOP73, OF ACCELERATED AGEING AND APP TRANSGENIC MICE, NEURONAL CULTURES, AND CEREBROSPINAL FLUID SAMPLES FROM PATIENTS AT DIFFERENT STAGES OF ALZHEIMER¿S DISEASE._x000D_ USING DIFFERENT MORPHOLOGICAL, BIOCHEMICAL AND METABOLIC APPROACHES, WE INTEND: A) TO CHARACTERIZE THE POTENTIAL MECHANISMS OF P73 REGULATION IN RELEVANT PROTEINS FOR NEURONAL SURVIVAL, SUCH AS REELIN AND KLOTHO, NEUROTROPHIC RECEPTORS OF INSULIN GROWTH FACTOR AND ESTROGENS, IGF-1R AND ER, AND ITS CORRELATION WITH ALZHEIMER NEURODEGENERATIVE PROCESSES; B) TO ELUCIDATE THE POTENTIAL INFLUENCE OF ALTERATIONS IN LIPID RAFT MICRODOMAINS IN THE ACTIVITY OF THESE PROTEINS DURING NEURONAL AGEING; C) TO IDENTIFY THE MOLECULAR AND METABOLIC EVENTS IN LIPID RAFTS ASSOCIATED WITH THE PROTEIN MARKERS OF THE STUDY, USING CEREBROSPINAL FLUID SAMPLES AND EXOSOMES ISOLATED FROM ALZHEIMER¿S DISEASE PATIENTS AT DIFFERENT STAGES. _x000D_ THE PROPOSED APPROACHES WILL ALLOW US TO CHARACTERIZE RELEVANT ASPECTS OF BRAIN AGEING AND THE ASSOCIATED NEUROPATHOLOGIES, AND WILL PROVIDE INNOVATIVE TOOLS FOR EARLY DIAGNOSIS. MOREOVER, IT IS EXPECTED THAT THESE RESULTS WILL ALLOW UNDERSTANDING THE MOLECULAR AND CELLULAR CHANGES TAKING PLACE IN NEURAL CELLS ASSOCIATED WITH AGEING, AS HALLMARKS OF NEURODEGENERATIVE PROCESSES. (English)
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San Cristóbal de La Laguna
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Identifiers
SAF2017-84454-R
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