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SAF2012-40011-C02-01

Financiado

CONTROL POR PARP-1 DE LA AUTOPHAGIA TUMORAL: IMPLICACIONES EN LA TRANSFORMACION...

CONTROL POR PARP-1 DE LA AUTOPHAGIA TUMORAL: IMPLICACIONES EN LA TRANSFORMACION MALIGNA Y EN LA RESPUESTA AL TRATAMIENTO REGIONS WITHIN SOLID TUMOURS EXPERIENCE MILD TO SEVERE O2 DEPRIVATION OWING TO ABERRANT VASCULAR FUNCTION, ALTERED CELLULAR METABOLISM, AS WELL AS INCREASED RESISTANCE TO RADIATION AND CHEMOTHERAPY. HYPOXIC CONDITIONS EVENTUALLY A... ver más

01/01/2012

CSIC

152K€

Presupuesto del proyecto: 152K€

Líder del proyecto

AGENCIA ESTATAL CONSEJO SUPERIOR DE INVESTIGA... No se ha especificado una descripción o un objeto social para esta compañía.

TRL 2-3 | 552M€

Financiación concedida El organismo AGENCIA ESTATAL DE INVESTIGACIÓN notifico la concesión del proyecto el día 2012-01-01 No tenemos la información de la convocatoria

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CSIC

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Líder del proyecto

AGENCIA ESTATAL CONSEJO SUPERIOR DE INVESTIGA... No se ha especificado una descripción o un objeto social para esta compañía.

TRL 2-3 | 552M€

Presupuesto del proyecto 152K€

Descripción del proyecto REGIONS WITHIN SOLID TUMOURS EXPERIENCE MILD TO SEVERE O2 DEPRIVATION OWING TO ABERRANT VASCULAR FUNCTION, ALTERED CELLULAR METABOLISM, AS WELL AS INCREASED RESISTANCE TO RADIATION AND CHEMOTHERAPY. HYPOXIC CONDITIONS EVENTUALLY ALSO FAVOURS TUMOR PROGRESSION AND METASTASIS. POLY(ADP-RIBOSE) POLYMERASE-1 (PARP-1) IS AN ABUNDANT AND UBIQUITOUS NUCLEAR ENZYME WITH BIOCHEMICAL PROPERTIES THAT MAKE IT IDEALLY SUITED FOR THE REGULATION OF NUCLEAR PROCESSES. ALTHOUGH ORIGINALLY CHARACTERIZED AS A KEY FACTOR IN DNA REPAIR PATHWAYS, A WEALTH OF STUDIES HAVE DEMONSTRATED A ROLE FOR PARP-1 IN THE REGULATION OF GENE EXPRESSION. RESULTS FROM DIFFERENT GROUPS INCLUDING OURS, HAVE SHOWN THAT PARP-1 IS ABLE TO MODULATE THE TRANS-ACTIVATION OF MULTIPLE GENES INVOLVED IN TUMOR PROGRESSION, AMONG THEM, GENES INVOLVED IN TUMOR RESPONSE TO HYPOXIA AND ANGIOGENESIS. PARP-1 POTENTIATE HYPOXIA-INDUCIBLE FACTOR  (HIF-AND PARTICULARLY HIF2) TO UP-REGULATE HYPOXIA-INDUCED GENE EXPRESSION. THE PROCESS OF EPITHELIAL-MESENCHIMA TRANSITION (EMT) IS CRUCIAL FOR CANCER PROGRESSION AND METASTASIS. UNPUBISHED RESULTS FROM OUR GROUP SUGGEST THAT THE EXPRESSION AND ACTIVITY OF SNAIL-1, A CRITICAL REGULATOR OF EMT, AND THE LEVELS OF E-CADHERIN ARE ALSO MODULATED BY PARP. TUMOR HYPOXIA IS LINKED TO INCREASED METASTATIC POTENTIAL, BUT THE MOLECULAR MECHANISMS COUPLING HYPOXIA TO METASTASIS ARE POORLY UNDERSTOOD. INCREASING EVIDENCES IMPLICATE HIF FUNCTION IN THE ACQUISITION OF METASTATIC CHARACTERISTICS, LIKE EMT, CELL DETACHMENT, INVASION AND TUMOR CELL SEEDING. IN THIS PROJECT WE PROPOSE THAT INHIBITION OF PARP-1, THROUGH ITS ABILITY TO MODULATE HYPOXIC RESPONSE AND SNAIL ACTIVATION, MIGHT BE A POTENTIAL TARGET TO AVOID TUMOR METASTASIS. THE AIMS OF THE PRESENT PROJECT CAN BE SUMMARIZED AS FOLLOWS: TO GAIN INSIGHTS INTO THE CONNECTION BETWEEN PARP-1 AND THE MACHINERY OF RESPONSE TO HYPOXIA, AND IN PARTICULAR WITH THE STUDY IN DEPTH OF THE HIF-2ALPHA PROMOTER , AND THE GENERATION OF DOUBLE KNOCKOUT MICE FOR PARP-1 AND HIF-2 TO EVALUATE THE CONSEQUENCES OF PARP INHIBITION DURING ANGIOGENESIS ON PROTEOMIC AND GENOMIC PROFILES OF HUVEC CELLS IN VITRO. TO SHOW THAT PARP-1 SIGNALLING IS REQUIRED TO CONVERT THE HYPOXIC STIMULUS INTO EPITHELIALMESENCHYMAL TRANSITION (EMT), INCREASED MOTILITY, AND INVASIVENESS, THROUGH ITS INVOLVEMENT IN SNAIL ACTIVATION AND E-CADHERIN EXPRESSION. TO ANALYZE THE INTERACTION BOTH PHYSICAL AND FUNCTIONAL BETWEEN SNAIL-1 AND PARP-1, INCLUDING POLY(ADP-RYBOSILATIONS) PROFILES OF SNAIL AND SNAIL-RELATED CO-FACTORS. TO CHARACTERIZE HOW THE INHIBITION OF PARP MIGHT ABROGATE HYPOXIA-INDUCED EMT AND INVASION IN A MURINE MODEL OF METASTASIC MELANOMA USING THE IN VIVO VISUALISATION TECHNIQUE TO EVALUATE TUMOR GROWTH.

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