REPLICATION AND TRANSCRIPTION OF MITOCHONDRIAL DNA AS THE CENTRAL MECHANISM OF THE PATHOLOGICAL SEQUENCE LEADING TO NEURODEGENERATION. (Q3136083)

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Project Q3136083 in Spain
Language Label Description Also known as
English
REPLICATION AND TRANSCRIPTION OF MITOCHONDRIAL DNA AS THE CENTRAL MECHANISM OF THE PATHOLOGICAL SEQUENCE LEADING TO NEURODEGENERATION.
Project Q3136083 in Spain

    Statements

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    121,000.0 Euro
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    242,000.0 Euro
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    50.0 percent
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    1 January 2018
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    31 December 2020
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    AGENCIA CONSEJO SUPERIOR DE INVESTIGACIONES CIENTIFICAS
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    41°22'58.40"N, 2°10'38.75"E
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    08019
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    LAS ENFERMEDADES NEURODEGENERATIVAS PUEDEN TENER DIFERENTES CAUSAS Y UNO DE LOS PRINCIPALES OBJETIVOS DE LA INVESTIGACION ACTUAL ES IDENTIFICAR UN MECANISMO BIOQUIMICO COMUN CENTRAL EN EL QUE CONVERGEN. LA MAYORIA DE CAUSAS DE LAS ENFERMEDADES NEURODEGENERATIVAS SON AUN DESCONOCIDAS, PERO LAS MUTACIONES GENETICAS QUE PRODUCEN NEURODEGENERACION EN FAMILIAS PROPORCIONAN UN MODELO EXPERIMENTAL ROBUSTO PARA IDENTIFICAR LOS MECANISMOS BIOQUIMICOS CENTRALES DEL PROCESO NEURODEGENERATIVO. LA HIPOTESIS DEL PRESENTE PROYECTO ES QUE LA ALTERACION DE LA REGULACION DEL ADN MITOCONDRIAL (MTDNA) ES UN MECANISMO CENTRAL COMUN EN LA CADENA PATOLOGICA DEL PROCESO NEURODEGENERATIVO. SIN EMBARGO, EL ESTUDIO DE LA REPLICACION Y LA TRANSCRIPCION DEL MTDNA HA ESTADO LIMITADO POR LA DIFICULTAD DE MEDIR CON PRECISION EL NUMERO DE COPIAS DE GENOMA MITOCONDRIAL. RECIENTEMENTE HEMOS DESARROLLADO UN METODO LLAMADO SELFIE-DPCR QUE PERMITE LA CUANTIFICACION EN NUMEROS ABSOLUTOS DEL NUMERO DE TRANSCRITOS MITOCONDRIALES EN RELACION CON SU PROPIA CADENA DE TRANSCRIPCION EN EL MTDNA. ADEMAS, EN NUESTROS PROYECTOS ANTERIORES, HEMOS DESCUBIERTO QUE UNA DISMINUCION DEL CONTENIDO DE MTDNA CIRCULANTE EN EL LIQUIDO CEFALORRAQUIDEO (LCR) PRECEDE A LA MANIFESTACION DE LA ENFERMEDAD DE ALZHEIMER FAMILIAR, MIENTRAS QUE UN AUMENTO EN EL CONTENIDO DE MTDNA EN EL LCR SE ASOCIA CON PARKINSON EN PACIENTES CON MUTACIONES EN EL GEN LRRK2. SOBRE LA BASE DE ESTOS RESULTADOS ANTERIORES, PLANTEAMOS LA HIPOTESIS DE QUE LA ALTERACION EN EL BALANCE ENTRE LA REPLICACION Y LA DEGRADACION DE MTDNA POR LOS SISTEMAS DE CONTROL DE CALIDAD MITOCONDRIAL DETERMINA EL TIPO DE PROCESO NEURODEGENERATIVO. NO OBSTANTE, LOS SISTEMAS DE REGULACION DEL NUMERO DE COPIAS Y DE LA EXPRESION DEL MTDNA AUN NO SE CONOCEN EN PROFUNDIDAD. EN EL PRESENTE PROYECTO PROPONEMOS INVESTIGAR LA REGULACION DE LA TRANSCRIPCION Y LA REPLICACION DE MTDNA EN MODELOS GENETICOS DE LAS ENFERMEDADES DE ALZHEIMER Y PARKINSON. LOS OBJETIVOS ESPECIFICOS INCLUYEN: 1) ESTUDIAR LA INFLUENCIA DE LOS SISTEMAS DE CONTROL DE CALIDAD MITOCONDRIAL EN LA LIBERACION DE MTDNA EN EL ESPACIO EXTRACELULAR, 2) MEDIR LA REPLICACION Y TRANSCRIPCION DE MTDNA POR SELFIE-DPCR EN MODELOS GENETICOS Y 3) CARACTERIZAR EL MAPA DE TRANSCRIPCION GENICA DE LA VIA DE SEÑALIZACION ANTEROGRADA NUCLEAR-MITOCONDRIAL INDUCIDO POR UNA MUTACION PATOGENICA DEL GEN APP UTILIZANDO EL METODO SELFIE ACOPLADO A SECUENCIACION PARALELA MASIVA SEGUIDO DE VALIDACION POR SELFIE-DPCR. LOS RESULTADOS NOS PERMITIRAN CONTRASTAR LA HIPOTESIS DE QUE LA REGULACION DEL ADN MITOCONDRIAL ES UN MECANISMO CLAVE EN EL PROCESO NEURODEGENERATIVO Y QUE SU NORMALIZACION PUEDE EVITAR LA NEURODEGENERACION. (Spanish)
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    NEURODEGENERATIVE DISEASES MAY HAVE DIFFERENT CAUSES AND ONE OF THE MAIN OBJECTIVES OF CURRENT RESEARCH IS TO IDENTIFY A COMMON CENTRAL BIOCHEMICAL MECHANISM ON WHICH THEY CONVERGE. MOST OF THE CAUSES OF NEURODEGENERATIVE DISEASES ARE STILL UNKNOWN, BUT GENETIC MUTATIONS THAT PRODUCE NEURODEGENERATION IN FAMILIES PROVIDE A ROBUST EXPERIMENTAL MODEL TO IDENTIFY THE CENTRAL BIOCHEMICAL MECHANISMS OF THE NEURODEGENERATIVE PROCESS. THE GENERAL HYPOTHESIS OF THE PRESENT PROJECT IS THAT ALTERED REGULATION OF MITOCHONDRIAL DNA (MTDNA) IS A COMMON CENTRAL MECHANISM IN THE PATHOLOGICAL CHAIN OF THE NEURODEGENERATIVE PROCESS. HOWEVER, THE STUDY OF MTDNA REPLICATION AND TRANSCRIPTION HAS BEEN LIMITED BY THE DIFFICULTY OF ACCURATELY MEASURING THE NUMBER OF MITOCHONDRIAL GENOME COPIES. WE HAVE RECENTLY DEVELOPED A METHOD CALLED SELFIE-DPCR THAT ALLOWS ABSOLUTE QUANTIFICATION OF THE NUMBER OF MITOCHONDRIAL TRANSCRIPTS RELATIVE TO THEIR OWN TRANSCRIPTION CHAIN IN THE MTDNA. FURTHERMORE, IN OUR EARLIER PROJECTS, WE HAVE FOUND THAT A DECREASE IN CIRCULATING MTDNA CONTENT IN CEREBROSPINAL FLUID (CSF) PRECEDES THE MANIFESTATION OF FAMILIAL ALZHEIMER'S DISEASE, WHILE AN INCREASE IN THE CSF CONTENT OF MTDNA IS ASSOCIATED WITH PARKINSON'S DISEASE IN PATIENTS WITH MUTATIONS IN THE LRRK2 GENE. BASED ON THESE PREVIOUS RESULTS, WE HYPOTHESIZE THAT ALTERATION IN THE BALANCE BETWEEN MTDNA REPLICATION AND DEGRADATION BY MITOCHONDRIAL QUALITY CONTROL SYSTEMS DETERMINES THE TYPE OF NEURODEGENERATIVE PROCESS. NEVERTHELESS, THE SYSTEMS THAT REGULATE THE NUMBER OF MTDNA COPIES AND THEIR TRANSCRIPTION ARE NOT WELL KNOWN YET. IN THE PRESENT PROJECT WE PROPOSE TO INVESTIGATE THE REGULATION OF TRANSCRIPTION AND MTDNA REPLICATION IN GENETIC MODELS OF ALZHEIMER'S AND PARKINSON'S DISEASES. SPECIFIC OBJECTIVES INCLUDE: 1) TO STUDY THE INFLUENCE OF MITOCHONDRIAL QUALITY CONTROL SYSTEMS ON THE RELEASE OF MTDNA IN THE EXTRACELLULAR SPACE, 2) TO MEASURE REPLICATION AND TRANSCRIPTION OF MTDNA BY SELFIE-DPCR IN GENETIC MODELS, AND 3) TO CHARACTERIZE THE GENE TRANSCRIPTION MAP OF THE MITOCHONDRIAL NUCLEAR ANTEROGRADE SIGNALING PATHWAY EVOKED BY A PATHOGENIC APP GENE MUTATION USING SELFIE METHOD COUPLED TO TO MASSIVE PARALLEL SEQUENCING FOLLOWED BY VALIDATION WITH SELFIE-DPCR. THE RESULTS WILL ALLOW US CONTRASTING THE HYPOTHESIS THAT REGULATION OF MITOCHONDRIAL DNA IS A KEY MECHANISM IN THE NEURODEGENERATIVE PROCESS AND THAT ITS NORMALIZATION MAY PREVENT NEURODEGENERATION. (English)
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    Barcelona
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    Identifiers

    SAF2017-89791-R
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