DITERPENES AS NEW MODELS OF PHARMACOS IN NEURONAL REGENERATION THERAPIES (Q3145165): Difference between revisions
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36°31'43.28"N, 6°11'24.79"W
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Revision as of 10:32, 9 October 2021
Project Q3145165 in Spain
| Language | Label | Description | Also known as |
|---|---|---|---|
| English | DITERPENES AS NEW MODELS OF PHARMACOS IN NEURONAL REGENERATION THERAPIES |
Project Q3145165 in Spain |
Statements
43,560.0 Euro
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54,450.0 Euro
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80.0 percent
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1 January 2019
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31 December 2022
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UNIVERSIDAD DE CADIZ
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36°31'43.28"N, 6°11'24.79"W
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11028
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LOS TRASTORNOS DEL SISTEMA NERVIOSO CENTRAL DE DIFERENTES ETIOLOGIAS SON MUY FRECUENTES ENTRE LA POBLACION EUROPEA Y PROVOCAN UN ELEVADO COSTO POR PACIENTE. ESTE TIPO DE TRASTORNOS CAUSA DAÑO CEREBRAL Y PRODUCE MUERTE NEURONAL Y DEFICITS COGNITIVOS IRREVERSIBLES O ALTERACION SENSITIVO-MOTORA. ACTUALMENTE NO HAY UN TRATAMIENTO EFECTIVO DISPONIBLE PARA COMPENSAR LA PERDIDA NEURONAL. EL DESCUBRIMIENTO DE LA NEUROGENESIS EN EL CEREBRO ADULTO, QUE REVELA LA CAPACIDAD DEL SNC PARA GENERAR NUEVAS NEURONAS A PARTIR DE CELULAS MADRE NEURALES (NSC), HA ABIERTO UNA NUEVA PERSPECTIVA EN EL DESARROLLO DE TERAPIAS PARA ESTE TIPO DE TRASTORNOS. SIN EMBARGO, EL CEREBRO DE LOS MAMIFEROS TIENE UNA LIMITADA CAPACIDAD DE AUTORREPARACION Y REGENERACION NEURONAL. EL DESARROLLO DE NUEVAS ESTRATEGIAS DISEÑADAS PARA SUPERAR ESTA LIMITACION PODRIA TRANSFORMAR LA FORMA DE TRATAR A LOS PACIENTES CON UNA VARIEDAD CONSIDERABLE DE TRASTORNOS NEUROLOGICOS. EN UNA PROPUESTA ANTERIOR, NUESTRO GRUPO HA ENCONTRADO QUE LA ACTIVIDAD MODULADORA DE ISOZIMAS DE PKC ESPECIFICAS POR DITERPENOS CON ESQUELETO DE LATIRANO (INGOLES) O TIGLIANO (FORBOLES Y 12-DESOXIFORBOLES) CONDUCE A LA FORMACION DE NUEVAS NEURONAS MADURAS EN LESIONES Y EN NICHOS NEUROGENICOS. HEMOS ENCONTRADO QUE DISTINTOS ESTERES DE FORBOL E INGOL PRODUCEN DISTINTAS RESPUESTA BIOLOGICA, QUEDANDO POR ESTABLECER, EN UNA BASE MAS AMPLIA, LA RELACION ENTRE LA NATURALEZA DE LOS GRUPOS ESTER Y LA CAPACIDAD DE LOS COMPUESTOS PARA ACTIVAR ISOENZIMAS PKC ESPECIFICAS._x000D_ INGOLES Y 12-DESOXIFORBOLES PUEDEN OBTENERSE, EN MUY PEQUEÑA CANTIDAD, DE PLANTAS DE LA FAMILIA EUPHORBIACEAE. ESTE ES EL CASO DE ER272 Y EOF2, QUE SON NECESARIOS PARA EL DESARROLLO DEL SUBPROYECTO 1. PARA SU SUMINISTRO, PROCEDERIAMOS A AISLARLOS DE FUENTES CONOCIDAS. SI BIEN, PARA UN DESARROLLO ADICIONAL COMO AGENTES TERAPEUTICOS, ES NECESARIO EL HALLAZGO DE FUENTES MAS ACCESIBLES PARA LO QUE PROPONEMOS EXPLORAR LA PRODUCCION DE DITERPENOS RELEVANTES POR MICROORGANISMOS ENDOFITOS. _x000D_ POR OTRO LADO, PROPONEMOS REALIZAR TRANSFORMACIONES QUIMICAS, ENZIMATICAS O MICROBIOLOGICAS DE FORBOLES, 12-DESOXIFORBOLES E INGOLES, PREVIAMENTE AISLADOS DE FUENTES NATURALES Y EVALUAR LOS COMPUESTOS SEMISINTETICOS, CON EL FIN DE ESTABLECER LAS CARACTERISTICAS ESTRUCTURALES ASOCIADAS A LA PROMOCION DE TUMOR, A LA PROLIFERACION O DIFERENCIACION A NEURONA DE NSC Y ASI PODER OBTENER COMPUESTOS CON MEJOR PERFIL TERAPEUTICO. _x000D_ LA BIOTRANSFORMACION DE PRODUCTOS NATURALES, ES UNA METODOLOGIA BIEN ESTABLECIDA PARA LA INTRODUCCION DE GRUPOS FUNCIONALES EN POSICIONES INACTIVADAS. ADEMAS LAS TRANSFORMACIONES CON HONGOS SE EMPLEAN COMO MODELO DE METABOLISMO EN FASE I DE FARMACOS, LO QUE MUESTRA MUCHAS VENTAJAS SOBRE EL USO DE MODELOS ANIMALES. INTENTOS PREVIOS DE BIOTRANSFORMACIONES DE FORBOLES NO CONDUJERON A PRODUCTOS DE TRANSFORMACION LO QUE PUEDE DEBERSE AL USO DE MICROORGANISMOS INADECUADOS, O A LA NECESIDAD DE SISTEMAS ENZIMATICOS MAS ESPECIFICOS. UNA ALTERNATIVA, PARA EXPLORAR LA FASE I DEL METABOLISMO, ES EMPLEAR ENZIMAS UNIDAS A MEMBRANAS MICROSOMALES DE LEVADURAS. A TRAVES DE LA COLABORACION CON LA UNIVERSIDAD DE MONTFORT, NUESTRO GRUPO TIENE ACCESO A UNA COLECCION DE CITOCROMOS P450 RECOMBINANTES HUMANAS (CYPS), CLONADAS EN LEVADURAS, INCLUIDAS LAS DEL CEREBRO. PROPONEMOS SU USO TANTO PARA EVALUAR LA RESPUESTA, SOBRE CYPS SELECCIONADAS, DE COMPUESTOS PREPARADOS EN ESTE PROYECTO, COMO PARA MODELAR, CON MAYOR FIDELIDAD, SU METABOLISMO DE FASE I EN EL CEREBRO. (Spanish)
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ACUTE OR CHRONIC CENTRAL NERVOUS SYSTEM DISORDERS OF DIFFERENT ETIOLOGIES SUCH AS CEREBROVASCULAR, TRAUMATIC OR NEURODEGENERATIVE ARE VERY FREQUENT AMONG THE EUROPEAN POPULATION AND RESULT IN AN ELEVATED COST PER PATIENT. THIS TYPE OF DISORDERS CAUSE BRAIN DAMAGE PRODUCING NEURONAL DEATH AND IRREVERSIBLE COGNITIVE DEFICITS OR SENSORY-MOTOR ALTERATION. NO EFFECTIVE TREATMENT IS CURRENTLY AVAILABLE TO COMPENSATE NEURONAL LOSS; HOWEVER, THE DISCOVERY OF NEUROGENESIS IN THE ADULT BRAIN REVEALING THE CAPACITY OF THE CNS TO GENERATE NEW NEURONS FROM NEURAL STEM CELLS (NSC) HAS LED TO A NEW PERSPECTIVE IN THE DEVELOPMENT OF THERAPIES FOR THIS TYPE OF DISORDERS. YET THE MAMMALIAN BRAIN HAS A LIMITED CAPACITY FOR SELF-REPAIR AND NEURONAL REGENERATION, THE DEVELOPMENT OF NEW STRATEGIES DESIGNED TO OVERCOME THIS LIMITATION MAY TRANSFORM HOW WE COULD TREAT PATIENTS WITH A CONSIDERABLE VARIETY OF NEUROLOGICAL DISORDERS. IN A PREVIOUS PROPOSAL, WE HAVE FOUND THAT MODULATING ACTIVITY OF SPECIFIC PKC ISOZYMES BY DITERPENE COMPOUNDS (PHORBOL AND LATHYRANES) LEADS TO THE FORMATION OF NEW MATURE NEURONS IN INJURIES AND IN NEUROGENIC NICHES. WE FOUND THAT THE NATURE OF THE SIDE CHAINS ON PHORBOLS AND LATHYRANES, LEAD TO A MODULATION OF THEIR BIOLOGICAL RESPONSE. THEREFORE, IT IS IMPORTANT TO ESTABLISH, ON A WIDER BASE, THE RELATIONSHIP BETWEEN THEIR STRUCTURE AND THEIR ABILITY TO ACTIVATE SPECIFIC PKC ISOZYMES. _x000D_ THESE KIND OF DITERPENES CAN BE OBTAINED, IN MINUTE AMOUNTS, FROM PLANTS BELONGING TO EUPHORBIACEAE FAMILY. THIS IS THE CASE FOR ER272, EOF2, WHICH ARE NEEDED FOR THE DEVELOPMENT OF SUBPROJECT 1. ISOLATION FROM ADEQUATE SOURCES WILL BE CARRIED OUT IN ORDER TO MEET THE SUPPLY REQUIREMENTS. NEVERTHELESS, ANY FURTHER DEVELOPMENT AS THERAPEUTIC AGENTS FOR THESE KIND OF COMPOUNDS REQUIRES THE FINDING OF MORE ACCESSIBLE SOURCES. WE HEREIN PROPOSE TO EXPLORE ENDOPHYTIC MICROORGANISMS AS A NEW SOURCE OF RELEVANT DITERPENES. _x000D_ ON THE OTHER HAND, IN ORDER TO OBTAIN COMPOUNDS WITH A BETTER THERAPEUTIC PROFILE, CHEMICAL, ENZYMATIC AND MICROBIOLOGICAL TRANSFORMATIONS ON PHORBOLS AND LATHYRANES, PREVIOUSLY ISOLATED FROM NATURAL SOURCES, WILL PERFORMED, AND SEMISYNTHETIC COMPOUNDS WILL BE EVALUATED WITH THE AIM TO FIND THE STRUCTURAL FEATURES ASSOCIATED WITH TUMOR PROMOTION (TO BE AVOIDED), NPC PROLIFERATION OR NPC DIFFERENTIATION INTO NEURONS. _x000D_ MICROBIAL BIOTRANSFORMATION OF NATURAL PRODUCTS IS AN ESTABLISHED METHODOLOGY FOR THE INTRODUCTION OF FUNCTIONAL GROUPS AT INACTIVATED POSITIONS. FURTHERMORE, FUNGAL BIOTRANSFORMATION HAVE LONG BEEN ESTABLISHED AS A MODEL OF PHASE I METABOLISM OF DRUGS AND SHOW ADVANTAGES TO THE USE OF ANIMAL MODELS. PREVIOUS RESULTS FROM THE BIOTRANSFORMATION OF SELECTED PHORBOLS BY FUNGI SHOW AN INTRIGUING SCARCITY OF BIOTRANSFORMATION PRODUCTS. THIS MAY BE DUE TO THE USE OF INADEQUATE MICROORGANISMS AS MODELS, OR THE NEED OF MORE SPECIFIC ENZYMATIC SYSTEMS. AN ALTERNATIVE TO THE USE OF MICROBIAL SYSTEMS TO EXPLORE PHASE I METABOLISM, IS THE EMPLOYMENT OF ACTIVE MICROSOME-BOUND ENZYMES ISOLATED FROM RECOMBINANT BAKER'S YEAST. THROUGH A COLLABORATION WITH DE MONTFORT UNIVERSITY (UK), WE HAVE ACCESS TO A COLLECTION OF RECOMBINANT HUMAN CYTOCHROME P450 (CYPS), INCLUDING THOSE FOUND IN THE BRAIN. WE PROPOSE TO USE THEM BOTH TO TEST THE INHIBITORY (OR AGONIST) RESPONSE ON SELECTED CYPS OF SPECIFIC COMPOUNDS TO BE PREPARED IN THIS PROJECT, AND TO MODEL, MORE FAITHFULLY, THE PHASE I METABOLISM OF SELECTED BIOACTIVE COMPOUNDS IN THE BRAIN. (English)
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Puerto Real
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Identifiers
RTI2018-099908-B-C22
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