Innovating Works

SAF2012-39852-C02-02

Financiado
INTERACCION SIRTUINA 1-AMPK-MTOR EN LOS PROCESOS DE FRAGILIDAD MITOCONDRIAL COMO...
INTERACCION SIRTUINA 1-AMPK-MTOR EN LOS PROCESOS DE FRAGILIDAD MITOCONDRIAL COMO DIANA PARA LA PREVENCION DE LA NEURODEGENERACION: IMPLICACION EN LA ENFERMEDAD DE ALZHEIMER THE INTERPLAY BETWEEN SIRTUIN 1 AND AMPK IS RELEVANT BECAUSE THESE TWO MOLECULES ARE THE TWO KEY ENERGY SENSOR SYSTEMS THAT REGULATE CELL SURVIVAL, PROLIFERATION AND SENESCENCE. IT HAS BEEN PROPOSED THAT THE ANTI-AGEING ACTIVITY O... THE INTERPLAY BETWEEN SIRTUIN 1 AND AMPK IS RELEVANT BECAUSE THESE TWO MOLECULES ARE THE TWO KEY ENERGY SENSOR SYSTEMS THAT REGULATE CELL SURVIVAL, PROLIFERATION AND SENESCENCE. IT HAS BEEN PROPOSED THAT THE ANTI-AGEING ACTIVITY OF SIRTUIN 1 IS A RESULT, IN PART, OF THE FINE-TUNING OF THE AMPK PATHWAY WHICH PREVENTS THE TRANSITION OF AN ORIGINAL PRO-SURVIVAL PROGRAM INTO A PRO-AGEING MECHANISM RESULTING IN SYSTEMIC DEGENERATION. THE PROCESS IS ELEGANTLY CONTROLLED BY A COMPLEX NETWORK INVOLVING MANY SIGNALING PROTEINS (AMPK, MTOR) AND BY THE RATIOS BETWEEN LOW-MOLECULAR-WEIGHT METABOLITES (E.G. NAD/NADH AND AMP/ATP). FINAL EFFECTOR MECHANISMS REGULATE MANY PRO-SURVIVAL PROCESSES, SUCH AS MITOCHONDRIAL BIOGENESIS AND AUTOPHAGY. IN CONCLUSION, ENERGY METABOLISM AND METABOLIC REGULATORS PLAY PIVOTAL ROLES IN CONTROLLING LONGEVITY AND CELLULAR SENESCENCE; HOWEVER THE PARTICIPATION AND SPECIFIC WEIGHT ON THESE PROCESSES ARE POORLY UNDERSTOOD IN THE CENTRAL NERVOUS SYSTEM, AND THE BENEFITS OF PHARMACOLOGICAL MODULATION OF SOME OF THESE PATHWAYS REMAIN UNCLEAR. HERE WE PROPOSE TO EXAMINE THE MECHANISMS OF NORMAL AND DISEASE-ASSOCIATED AGEING IN AN IN VIVO CONTEXT (SAMP8 AND 3XTG-AD MOUSE STRAINS), WITH THE AIM OF IDENTIFYING THE GENETIC AND BIOCHEMICAL CHANGE THAT MAY BE RELEVANT IN THE DEVELOPMENT OF DELETERIOUS PROCESSES THAT LEAD TO FRAILTY IN AGEING AND THEIR RELATIONSHIP WITH ALZHEIMER'S DISEASE (AD). RELEVANT ASPECTS AND MECHANISMS WILL BE ANALYZED FOR THEIR POTENTIAL TO TRIGGER AD-RELATED PATHOLOGY. TO THIS END, WE WILL USE AN ESTABLISHED MODEL OF SENESCENCE SAMP8 MICE, AN AD MOUSE MODEL (3XTG-AD) AND WE WILL DESIGN A CONTINUOUS PARADIGM MODEL SYSTEM OF INCREASED MITOCHONDRIAL FRAILTY: CONTROL MICE (SAMR1 AND NONTG (WILD TYPE FOR 3XTG-AD)); SAMR1 SUBJECTED TO A HIGH-FAT DIET; SENESCENCE-ACCELERATED MICE (SAMP8); SAMP8 SUBJECTED TO A HIGH-FAT DIET; AND TRANSGENIC AD MICE (3XTG-AD). THE MAIN OBJECTIVE WILL BE TO STUDY THE SIRTUIN 1-AMPK-MTOR PATHWAYS IN THE MOUSE MODELS OF CONTINUOUS AND PROGRESSIVE SENESCENCE AND AD, AND TO ESTABLISH THEIR PARTICIPATION IN THE MITOCHONDRIAL DYSFUNCTION THAT LEADS TO FRAILTY. TO RESCUE FRAIL MITOCHONDRIA WE WILL MODULATE THE SIRTUIN 1-AMPK-MTOR NETWORK USING PHARMACOLOGICAL TREATMENTS (RESVERATROL, MELATONIN AND OTHER SPECIFIC AGENTS) AND GENETIC TOOLS THAT INDUCE CHANGES IN SIRTUIN 1 EXPRESSION. WE WILL ALSO ANALYZE THE SIRTUIN 1-AMPK-MTOR PATHWAYS AND MARKERS OF MITOCHONDRIAL FUNCTION IN HUMAN TISSUE FROM VARIOUS STAGES OF AGEING AND IN AD PATIENTS (CONTROL SUBJECTS, SENILE SUBJECTS SHOWING AMYLOID PATHOLOGY, SUBJECTS DIAGNOSED AT EARLY STAGES OF BRAAK AND BRAAK WITH TAU PATHOLOGY AND THOSE WITH OVERT AD PATHOLOGY OF AMYLOID AND TAU). FINALLY, WE WILL ESTABLISH A CORRELATION BETWEEN WHOLE DATA FROM EXPERIMENTAL ANIMAL MODELS AND HUMAN TISSUE IN ORDER TO IDENTIFY NEW TARGETS FOR POTENTIAL THERAPEUTIC INTERVENTIONS AGAINST PATHOLOGICAL AGEING AND AD DEVELOPMENT. ver más
01/01/2012
CSIC
105K€
Perfil tecnológico estimado

Línea de financiación: concedida

El organismo AGENCIA ESTATAL DE INVESTIGACIÓN notifico la concesión del proyecto el día 2012-01-01
Presupuesto El presupuesto total del proyecto asciende a 105K€
Líder del proyecto
AGENCIA ESTATAL CONSEJO SUPERIOR DE INVESTIGA... No se ha especificado una descripción o un objeto social para esta compañía.
Perfil tecnológico TRL 2-3 552M