No label defined (Q3176759)
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Project Q3176759 in Spain
| Language | Label | Description | Also known as |
|---|---|---|---|
| English | No label defined |
Project Q3176759 in Spain |
Statements
348,480.0 Euro
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435,600.0 Euro
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80.0 percent
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1 January 2019
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31 December 2021
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UNIVERSIDAD DE SANTIAGO DE COMPOSTELA
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15078
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LA OBESIDAD Y SUS COMORBILIDADES ASOCIADAS ESTAN ALCANZANDO UNAS PROPORCIONES PANDEMICAS. ES POR TANTO DEMANDANTE INVESTIGAR Y COMPRENDER LOS MECANISMOS FISIOPATOLOGICOS QUE REGULAN EL BALANCE ENERGETICO. DATOS RECIENTES, MUCHOS DE ELLOS DE NUESTRO GRUPO, HAN SUGERIDO QUE, ADEMAS DE LOS MECANISMOS ENDOCRINOS Y NEUROENDOCRINOS CLASICOS, LA KINASA ACTIVADA POR AMPK (AMP-ACTIVATED PROTEIN KINASE, AMPK) EN EL HIPOTALAMO: 1) REGULA LA INGESTA DE ALIMENTOS; 2) CONTROLA EL METABOLISMO LIPIDICO PERIFERICO Y LA HOMEOSTASIS DE LA GLUCOSA Y 3) REGULA EL GASTO ENERGETICO A TRAVES DE LA MODULACION DEL PROGRAMA TERMOGENICO EN EL TEJIDO ADIPOSO PARDO (BROWN ADIPOSE TISSUE, BAT). LA CONCLUSION GLOBAL DE TODAS ESTAS EVIDENCIAS ES QUE LA MODULACION DE AMPK ES UN MECANISMO FISIOLOGICO CLAVE QUE REGULA EL BALANCE ENERGETICO. A PESAR DE ESTAS CERTEZAS, LOS DETALLES MOLECULARES Y CELULARES MEDIANTE LOS CUALES AMPK HIPOTALAMICA MODULA EL SISTEMA CENTRAL DE CONTROL DE ENERGIA, SON COMPLETAMENTE DESCONOCIDOS. ESTE PROYECTO SE CENTRA ELUCIDAR DICHOS MECANISMOS. EN CONCRETO, PLANTEAMOS QUE EL FENOTIPADO METABOLICO COMPLETO DE DOS MODELOS DE RATON KNOCKOUT (KO): 1) UNO DE LA ISOFORMA CATALITICA AMPKALPHA1 EN LAS NEURONAS POMC (PROOPIOMELANOCORTIN) DEL NUCLEO ARCUATO DEL HIPOTALAMO (ARC) Y 2) OTRO DE LA ISOFORMA CATALITICA AMPKALPHA2 EN LAS NEURONAS SF1 (STEREIDOGENIC FACTOR 1) DEL NUCLEO VENTROMEDIAL DEL HIPOTALAMO (VMH). ADEMAS, PLANTEAMOS EL ESTUDIO DE LAS INTERACCIONES ENTRE AMPKALPHA Y OTROS MECANISMOS IMPLICADOS EN LA REGULACION DEL BALANCE ENERGETICO, COMO EL METABOLISMO DE LOS ACIDOS GRASOS Y DE LAS CERAMIDAS, EL ESTRES DE RETICULO ENDOPLASMATICO (ER STRESS), LA SEÑALIZACION GLUTAMINERGICA Y LOS SISTEMAS DE NEUROPEPTIDOS HIPOTALAMICOS. EL FENOTIPADO METABOLICO DE ESTOS MODELOS GENETICAMENTE MODIFICADOS PERMITIRA CONOCER LAS ALTERACIONES EN EL BALANCE ENERGETICO (CENTRALES Y PERIFERICAS) ASOCIADAS A CAMBIOS EN LA ACTIVIDAD DE AMPK EN EL HIPOTALAMO. PARA ELLO, PLANTEAMOS EL USO DE DICHOS MODELOS MURINOS Y EXPERIMENTOS DE ACTIVACION Y ABLACION GENETICA BASADA EN LA ADMINISTRACION ESTEROTAXICA DE VIRUS EN EL HIPOTALAMO. LOS RESULTADOS OBTENIDOS DE ESTE PROYECTO CONDUCIRAN A LA IDENTIFICACION DE NUEVAS VIAS Y DIANAS PARA EL TRATAMIENTO DE LA OBESIDAD Y OTRAS PATOLOGIAS DEL BALANCE ENERGETICO. (Spanish)
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OBESITY AND ITS COMORBIDITIES ARE REACHING PANDEMIC PROPORTIONS. IT IS THEREFORE DEMANDING TO INVESTIGATE AND UNDERSTAND THE PATHOPHYSIOLOGICAL MECHANISMS THAT REGULATE ENERGY BALANCE. RECENT DATA, SOME OF THEM FROM OUR GROUP HAVE SUGGESTED THAT BESIDES THE CLASSIC ENDOCRINE AND NEUROENDOCRINE MECHANISMS, HYPOTHALAMIC AMP-ACTIVATED PROTEIN KINASE (AMPK): 1) REGULATES FOOD INTAKE; 2) CONTROLS THE PERIPHERAL LIPID METABOLISM AND GLUCOSE HOMEOSTASIS AND 3) REGULATES ENERGY EXPENDITURE THROUGH THE MODULATION OF THE THERMOGENIC PROGRAM IN THE BROWN ADIPOSE TISSUE (BAT). THE OVERALL CONCLUSION OF THIS EVIDENCE IS THAT THE MODULATION OF AMPK IS A KEY PHYSIOLOGICAL MECHANISM THAT REGULATES ENERGY BALANCE. DESPITE THESE DATA, THE MOLECULAR AND CELLULAR DETAILS BY WHICH HYPOTHALAMIC AMPK MODULATES THE CENTRAL SYSTEM CONTROLLING ENERGY BALANCE ARE COMPLETELY UNKNOWN. THIS PROJECT FOCUSES TO ELUCIDATE THESE MECHANISMS. SPECIFICALLY, WE PROPOSE THE COMPLETE METABOLIC PHENOTYPING OF TWO MODELS OF KNOCKOUT (KO) MICE: 1) ONE OF THE CATALYTIC ISOFORM AMPKALPHA1 IN THE POMC (PROOPIOMELANOCORTIN) NEURONS OF THE ARCUATE NUCLEUS OF THE HYPOTHALAMUS (ARC) AND 2) ANOTHER OF THE CATALYTIC ISOFORM AMPKALPHA2 IN THE SF1 NEURONS (STEREIDOGENIC FACTOR 1) OF THE VENTROMEDIAL NUCLEUS OF THE HYPOTHALAMUS (VMH). IN ADDITION, WE PROPOSE THE STUDY OF THE INTERACTIONS BETWEEN AMPKALPHA AND OTHER MECHANISMS INVOLVED IN THE REGULATION OF ENERGY BALANCE, SUCH AS THE METABOLISM OF FATTY ACIDS AND CERAMIDES, ENDOPLASMIC RETICULUM STRESS (ER STRESS), GLUTAMINERGIC SIGNALING AND HYPOTHALAMIC NEUROPEPTIDES. THE METABOLIC PHENOTYPING OF THESE GENETICALLY MODIFIED MODELS WILL ALLOW TO KNOW THE ALTERATIONS IN THE ENERGY BALANCE (CENTRAL AND PERIPHERAL) ASSOCIATED WITH CHANGES IN THE ACTIVITY OF AMPK IN THE HYPOTHALAMUS. TO DO THIS, WE PROPOSE THE USE OF THESE MURINE MODELS AND EXPERIMENTS OF ACTIVATION AND GENETIC ABLATION BASED ON THE STEREOTAXIC ADMINISTRATION OF VIRUSES IN THE HYPOTHALAMUS. THE RESULTS OBTAINED FROM THIS PROJECT WILL LEAD TO THE IDENTIFICATION OF NEW PATHWAYS AND TARGETS FOR THE TREATMENT OF OBESITY AND OTHER PATHOLOGIES OF THE ENERGY BALANCE. (English)
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Santiago de Compostela
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Identifiers
RTI2018-101840-B-I00
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