Descripción del proyecto
MANY BIOLOGICALLY IMPORTANT PROCESSES ARE REGULATED BY THE CN-NFAT PATHWAY, SUCH AS THE REGULATION AND DEVELOPMENT OF THE IMMUNE, VASCULAR AND NERVOUS SYSTEMS, THE MORPHOGENESIS OF THE HEART VALVES, MUSCLE DEVELOPMENT, LUNG MATURATION, AND FUNCTIONS OF PANCREATIC -CELLS, THIS PATHWAY IS ALSO INVOLVED IN PATHOPHYSIOLOGICAL PROCESSES SUCH AS THE MAINTENANCE OF THE LEUKEMIC PHENOTYPE, OSTEOPOROSIS, DIABETES AND HYPERTROPHY OF CARDIAC AND SKELETAL MUSCLE, WE HAVE RECENTLY IDENTIFIED AND CHARACTERIZED DOCKING REGIONS ON CN-INTERACTING PROTEINS WHOSE EXPRESSION AS PEPTIDES INTERFERES WITH THE ACTIVATION OF THE PATHWAY IN INTACT CELLS, WE PROPOSE TO USE LENTIVIRAL VECTORS ENCODING THESE SEQUENCES OR SIRNAS TARGETING INDIVIDUAL NFAT MEMBERS TO ANALYZE AND CHARACTERIZE THE ROLES OF THE NFAT-CN PATHWAY IN THE FOLLOWING PHYSIOLOGICAL AND PATHOPHYSIOLOGICAL SETTINGS:1,- INFLAMMATION, USING A MODEL OF COLLAGEN-INDUCED ARTHRITIS AND IN THE T LYMPHOCYTE ACTIVATION PROGRAM 2,- RETINAL ANGIOGENESIS AND ISCHEMIC RETINOPATHIES, VIA ANALYSIS OF IN VIVO MODELS OF PHYSIOLOGICAL ANGIOGENESIS (NORMAL RETINAL VASCULAR DEVELOPMENT) AND PATHOPHYSIOLOGICAL ANGIOGENESIS (MURINE RETINOPATHY OF PREMATURITY) AS WELL AS THE STUDY OF RCAN1-DEFICIENT MICE 3, THE GENE EXPRESSION PROGRAM INDUCED BY ANGIOTENSIN II IN VASCULAR SMOOTH MUSCLE CELLS (VSMCS) AND CARDIOMYOCYTES, USING GENOMIC AND PROTEOMIC APPROACHES, 4, ANGIOTENSIN II-INDUCED CARDIAC HYPERTROPHY IN VITRO AND IN VIVO, VIA THE ANALYSIS OF MOUSE MODELS OF HYPERTROPHY AND HYPERTENSION INDUCED BY MINIPUMP INFUSION OF ANG-II, WE ALSO PROPOSE TO TEST THE IDENTIFIED GENES IN HUMAN BIOPSIES FROM HEARTS OF PATIENTS UNDERGOING AORTIC STENOSIS SURGERYTHESE STUDIES MAY ALSO LEAD TO THE IDENTIFICATION OF THERAPEUTIC TARGETS FOR THE DEVELOPMENT OF DRUGS DISPLAYING IMMUNOSUPPRESSIVE PROPERTIES EQUIVALENT TO THOSE OF FK506 AND CSA BUT WITHOUT THEIR SEVERE SIDE EFFECTS, SUCH COMPOUNDS COULD THEREFORE BE USED TO TREAT PATHOLOGIES WHERE THE PATHWAY IS INVOLVED, IN ADDITION THE STUDY THAT WE PROPOSE MIGHT CONFIRM THE RELEVANCE OF NEW THERAPEUTIC TARGETS THAT WE HAVE RECENTLY IDENTIFIED BASED ON THE STUDY OF THE DOCKING REGIONS OF VARIOUS CN-INTERACTING PROTEINS, CALCINEURINA\NFAT\ACTIVACION DE LINFOCITOS\INFLAMACION\ANGIOGENESIS\RETINOPATIA\HIPERTENSION\HIPERTROFIA CARDIACA