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PID2019-105565RJ-I00

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ESTUDIO DEL INTERACTOMA DEL INFLAMASOMA Y SU RELEVANCIA CLINICA

THE INFLAMMASOMES ARE MOLECULAR STRUCTURES LOCALIZED IN THE CYTOSOL, WHICH ARE RESPONSIBLE OF IMMUNE SYSTEM ACTIVATION AFTER INFECTION OR TISSUE INJURY, THEY ARE MULTIPROTEIN COMPLEXES FORMED BY SENSORS (NLRS), THE ADAPTOR PROTEIN... ver más

01/01/2019

182K€

Presupuesto del proyecto: 182K€

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UNIVERSIDAD DE MURCIA No se ha especificado una descripción o un objeto social para esta compañía.

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Financiación concedida El organismo AGENCIA ESTATAL DE INVESTIGACIÓN notifico la concesión del proyecto el día 2019-01-01 No tenemos la información de la convocatoria

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Líder del proyecto

UNIVERSIDAD DE MURCIA No se ha especificado una descripción o un objeto social para esta compañía.

Total investigadores 911

Presupuesto del proyecto 182K€

Fecha límite de participación Sin fecha límite de participación.

Descripción del proyecto THE INFLAMMASOMES ARE MOLECULAR STRUCTURES LOCALIZED IN THE CYTOSOL, WHICH ARE RESPONSIBLE OF IMMUNE SYSTEM ACTIVATION AFTER INFECTION OR TISSUE INJURY, THEY ARE MULTIPROTEIN COMPLEXES FORMED BY SENSORS (NLRS), THE ADAPTOR PROTEIN ASC AND THE EFFECTOR PROTEINS CASPASE-1, -4, -5 AND -11, I HAVE RECENTLY IDENTIFIED A CRUCIAL ROLE THE INFLAMMASOME IN THE REGULATION OF HEMATOPOIESIS, BESIDES ITS WELL-KNOWN ROLE IN IMMUNITY, USING THE UNIQUE ADVANTAGE OF THE ZEBRAFISH MODEL, THUS, GENETIC AND PHARMACOLOGICAL INHIBITION OF THE DIFFERENT INFLAMMASOME COMPONENTS DECREASES NEUTROPHIL AND MACROPHAGE NUMBER AND CONCOMITANTLY INCREASED ERYTHROCYTE COUNTS, CONVERSELY, GENETIC ACTIVATION OF THE INFLAMMASOME INCREASES MYELOPOIESIS AND IMPAIRS ERYTHROPOIESIS, INTERESTINGLY, ALTHOUGH THE EMERGENCE OF HEMATOPOIETIC STEM AND PROGENITOR CELLS (HSPCS) WAS NOT AFFECTED, THE INFLAMMASOME IS INTRINSICALLY REQUIRED FOR THE MYELOID DIFFERENTIATION OF HSPCS, I ALSO FOUND THAT THIS MECHANISM IS EVOLUTIONARILY CONSERVED, AS PHARMACOLOGICAL INHIBITION OF THE INFLAMMASOME ALTERED ERYTHROID DIFFERENTIATION OF HUMAN CD34+ HSPCS AND K562 ERYTHROLEUKEMIC CELLS, USING COMPLEMENTARY BIOCHEMICAL TECHNIQUES, I FOUND THAT CASPASE-1 CLEAVAGE OF GATA1 AT RESIDUE D300 REGULATES BOTH EARLY MYELOID/ERYTHROID CHOICE AND TERMINAL ERYTHROID DIFFERENTIATION, MORE IMPORTANTLY, I DEVELOPED SEVERAL ZEBRAFISH AND MOUSE DISEASE MODELS OF NEUTROPHILIC INFLAMMATION AND ANEMIA AND DEMONSTRATED THAT PHARMACOLOGICAL INHIBITION OF THE INFLAMMASOME RESCUE ANEMIA IN ALL OF THEM, THESE RESULTS INDICATE THAT THE INFLAMMASOME PLAYS A MAJOR ROLE IN THE PATHOGENESIS OF NEUTROPHILIA AND ANEMIA OF CHRONIC DISEASES AND REVEAL NOVEL DRUGGABLE TARGETS FOR THERAPEUTIC INTERVENTIONS, IN VIEW OF THE SCIENTIFIC AND CLINICAL IMPACT OF THESE RESULTS, WHICH HAVE BEEN PUBLISHED AT THE PRESTIGIOUS JOURNSL IMMUNITY (IF 21,5) , WHERE I AM FIRST AND CORRESPONDING AUTHOR, I ENVISAGE THAT THE IDENTIFICATION OF THE SPECIFIC INTERACTOME OF HSPCS AND ERYTHROID PROGENITORS (EPS) WILL SHED LIGHT INTO THE MECHANISM OF INFLAMMASOME ASSEMBLY AND FUNCTION AND WILL ALSO UNCOVER NOVEL DISEASE BIOMARKERS AND THERAPEUTIC TARGETS, THEREFORE, IN THE PRESENT PROJECT I WILL TAKE ADVANTAGE OF MY EXPERTISE IN BIOCHEMISTRY, PROTEOMIC, CELL CULTURE AND ZEBRAFISH MODEL TO ADDRESS THE FOLLOWING AIMS: (I) TO VISUALIZE IN VIVO AT REAL TIME AND AT SINGLE CELL RESOLUTION THE ACTIVATION AND ASSEMBLY OF THE INFLAMMASOME IN HSPCS AND EPS AS WELL AS THE RELEASE OF INFLAMMASOME SPECK AND TAKEN UP BY HSPCS, (II) TO CHARACTERIZE THE RELEVANCE OF THE NLRP1 INFLAMMASOME IN HEMATOPOIESIS USING ZEBRAFISH AND HUMAN CD34+ HSPCS, AND (III) TO IDENTIFY THE INTERACTOME OF THIS INFLAMMASOME IN HSPCS AND EPS IN ZEBRAFISH USING IN VIVO BIOTINYLATION WHERE ASC AND CASPA ASSOCIATED PROTEINS (I,E, THE INFLAMMASOME INTERACTOME) WILL BE SELECTIVELY RECOVERED FROM HSPCS AND EPS EXPRESSING TAGGED ASC OR CASPA AND THE BACTERIAL BIOTIN LIGASE BIRA, THE MOST INTERESTING CANDIDATES WILL BE THEN VALIDATED IN HUMAN CD34+ HSPCS AND ERYTHROID CELL LINES, THE CLARIFICATION OF THE INFLAMMASOME INTERACTOME IN HSPCS AND EPS MAY UNCOVER NOVEL DIAGNOSTIC, PROGNOSIS AND THERAPEUTIC TARGETS WITH IMPORTANT CLINICAL IMPLICATIONS, INMUNIDAD\INFLAMACION\INFLAMASOMA\ANEMIA\TERAPIAS

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