STRUCTURAL DETERMINANTS AND THERMODYNAMICS OF CYTOTOXICITY OF BETA-AMYLOID OLIGOMERS. IMPLICATIONS FOR ALZHEIMER’S (Q3136802): Difference between revisions
Jump to navigation
Jump to search
(Created claim: summary (P836): AMYLOID AGGREGATION IS A SIGN OF IDENTITY OF NEUROPATOLOGIAS AND OTHER DISEASES WITH TREMENDOUS IMPACT, AMONG THEM ALZHEIMER’S DISEASE (AD). IT IS INCREASINGLY EVIDENT THAT THE NEURONAL DEATH ASSOCIATED WITH EA IS MAINLY INDUCED BY OLIGOMERS OF THE BETA-AMYLOID PEPTIDE (AB). HOWEVER, LITTLE IS KNOWN ABOUT THE MECHANISM OF FORMATION OF THESE OLIGOMERS, THEIR STRUCTURAL AND THERMODYNAMIC PROPERTIES, AND HOW THEY INDUCE THE BIOLOGICAL MECHANISMS OF...) |
(Changed label, description and/or aliases in en: translated_label) |
||
| label / en | label / en | ||
STRUCTURAL DETERMINANTS AND THERMODYNAMICS OF CYTOTOXICITY OF BETA-AMYLOID OLIGOMERS. IMPLICATIONS FOR ALZHEIMER’S | |||
Revision as of 13:39, 12 October 2021
Project Q3136802 in Spain
| Language | Label | Description | Also known as |
|---|---|---|---|
| English | STRUCTURAL DETERMINANTS AND THERMODYNAMICS OF CYTOTOXICITY OF BETA-AMYLOID OLIGOMERS. IMPLICATIONS FOR ALZHEIMER’S |
Project Q3136802 in Spain |
Statements
145,200.0 Euro
0 references
181,500.0 Euro
0 references
80.0 percent
0 references
1 January 2014
0 references
31 December 2017
0 references
UNIVERSIDAD DE GRANADA
0 references
37°10'24.60"N, 3°35'58.31"W
0 references
18087
0 references
LA AGREGACION AMILOIDE ES SEÑA DE IDENTIDAD DE NEUROPATOLOGIAS Y OTRAS ENFERMEDADES CON TREMENDO IMPACTO, ENTRE LAS DESTACA LA ENFERMEDAD DE ALZHEIMER (EA). CADA VEZ ES MAS EVIDENTE QUE LA MUERTE NEURONAL ASOCIADA A LA EA ES INDUCIDA PRINCIPALMENTE POR OLIGOMEROS DEL PEPTIDO BETA-AMILOIDE (AB). SIN EMBARGO, AUN SE SABE POCO SOBRE EL MECANISMO DE FORMACION DE ESTOS OLIGOMEROS, SUS PROPIEDADES ESTRUCTURALES Y TERMODINAMICAS, Y SOBRE COMO INDUCEN LOS MECANISMOS BIOLOGICOS DE SU TOXICIDAD. ESTA INFORMACION ES CRUCIAL PARA EL DESARROLLO DE FUTUROS FARMACOS O TERAPIAS EFICACES CONTRA LA EA._x000D_ ESTE PROYECTO SE BASA EN LOS RESULTADOS DE UN PROYECTO ANTERIOR (BIO2009-07317), EN EL CUAL SE HA DESARROLLADO UNA METODOLOGIA CINETICA PARA EL ANALISIS CUANTITATIVO DE LAS ETAPAS TEMPRANAS DE AGREGACION AMILOIDE, UTILIZANDO UN DOMINIO SH3 COMO SISTEMA MODELO. POR PRIMERA VEZ, HEMOS OBTENIDO PROPIEDADES TERMODINAMICAS Y ESTRUCTURALES SOBRE LAS ESPECIES MONOMERICAS Y OLIGOMERICAS QUE PRECEDEN A LOS NUCLEOS DE AGREGACION AMILOIDE._x000D_ DURANTE LAS FASES FINALES DEL PROYECTO ANTERIOR HEMOS EXTENDIDO ESTA METODOLOGIA AL ANALISIS DE LA AGREGACION DE AB. LOS RESULTADOS PRELIMINARES ESTAN EN MUY BUEN ACUERDO CON LAS PREDICCIONES DE NUESTRO MODELO CINETICO. HEMOS ENCONTRADO CONDICIONES EN LAS QUE LA FORMACION TEMPRANA DE OLIGOMEROS DE AB40 Y AB42 A PARTIR DE LOS MONOMEROS OCURRE RAPIDAMENTE Y SIN FASE DE LATENCIA; LOS OLIGOMEROS PARECEN TENER ESTRUCTURA AMILOIDE, SON DE TAMAÑO HETEROGENEO Y EVOLUCIONAN LENTAMENTE FORMANDO AGREGADOS PROTOFIBRILLARES MAYORES Y FIBRILLAS AMILOIDES._x000D_ SOBRE LA BASE DE ESTOS RESULTADOS, ESTE PROYECTO ESTA DIRIGIDO A EXPLORAR MAS A FONDO EL MECANISMO DE LA OLIGOMERIZACION DE A UTILIZANDO NUESTRA METODOLOGIA CON EL FIN DE INVESTIGAR LAS PROPIEDADES MOLECULARES Y FISICO-QUIMICAS DE ESTAS ESPECIES OLIGOMERICAS Y COMO EJERCEN SUS EFECTOS TOXICOS EN LAS CELULAS. MAS ESPECIFICAMENTE, LOS OBJETIVOS PRINCIPALES SON: I) ANALIZAR CUANTITATIVAMENTE LAS DIFERENCIAS CINETICAS Y TERMODINAMICAS ENTRE LA OLIGOMERIZACION DE AB40 Y AB42, ASI COMO OTRAS VARIANTES, MEZCLAS Y MUTANTES, BAJO DIVERSAS CONDICIONES EXPERIMENTALES; II) CARACTERIZAR LA DISTRIBUCION DE TAMAÑOS, MORFOLOGIA, ESTRUCTURA Y OTRAS PROPIEDADES BIOFISICAS Y TERMODINAMICAS DE LOS OLIGOMEROS DE AB A FIN DE COMPRENDER COMO ESTAS PROPIEDADES SE VEN INFLUIDAS POR EL MECANISMO DE FORMACION; III) INVESTIGAR Y COMPARAR LOS EFECTOS CITOTOXICOS DE DIFERENTES PREPARACIONES BIEN CARACTERIZADAS DE OLIGOMEROS DE AB PARA ESTABLECER UNA CONEXION ENTRE SUS PROPIEDADES BIOFISICAS Y SUS EFECTOS EN LAS CELULAS._x000D_ PARA LOGRAR ESTOS OBJETIVOS, PLANEAMOS AQUI UN ENFOQUE DE COLABORACION MULTIDISCIPLINAR BASADO EN NUESTRA EXPERIENCIA PREVIA EN UNA GRAN VARIEDAD DE METODOS BIOFISICOS Y BIOLOGICOS, INCLUYENDO VARIAS ESPECTROSCOPIAS, CALORIMETRIAS, RMN, MICROSCOPIA ELECTRONICA Y DE FUERZA ATOMICA, ETC. COLECTIVAMENTE, LA INFORMACION DERIVADA A PARTIR DE LOS EXPERIMENTOS BIOFISICOS PROPORCIONARA UNA SOLIDA BASE FISICOQUIMICA PARA INTERPRETAR LOS MECANISMOS BIOLOGICOS DE LA CITOTOXICIDAD DE AB. SE EXPLORARAN LA TOXICIDAD INDUCIDA POR OLIGOMEROS, LA VIABILIDAD CELULAR Y LOS MECANISMOS DE LA MUERTE CELULAR EN UNA LINEA CELULAR DE NEUROBLASTOMA HUMANO, TRATANDO DE IDENTIFICAR LAS RUTAS BIOQUIMICAS IMPLICADAS. MEDIANTE LA FUSION DE TODA ESTA VARIEDAD DE INFORMACION ESPERAMOS AMPLIAR EL CONOCIMIENTO DE LOS MECANISMOS MOLECULARES POR LOS QUE LOS OLIGOMEROS DE AB CONTRIBUYEN A LA APARICION Y EL DESARROLLO DE LA EA. (Spanish)
0 references
AMYLOID AGGREGATION IS A SIGN OF IDENTITY OF NEUROPATOLOGIAS AND OTHER DISEASES WITH TREMENDOUS IMPACT, AMONG THEM ALZHEIMER’S DISEASE (AD). IT IS INCREASINGLY EVIDENT THAT THE NEURONAL DEATH ASSOCIATED WITH EA IS MAINLY INDUCED BY OLIGOMERS OF THE BETA-AMYLOID PEPTIDE (AB). HOWEVER, LITTLE IS KNOWN ABOUT THE MECHANISM OF FORMATION OF THESE OLIGOMERS, THEIR STRUCTURAL AND THERMODYNAMIC PROPERTIES, AND HOW THEY INDUCE THE BIOLOGICAL MECHANISMS OF THEIR TOXICITY. This INFORMATION IS CRUCIAL FOR THE DEVELOPMENT OF FARMACY FUTURES OR Effective TERAPIES AGAINST EA._x000D_ This project is based on the results of an earlier project (BIO2009-07317), in which a cynetic methodology has been developed for the quantitious analysis of the amiloid aggregation, using a SH3 DOMINY AS MODEL SYSTEM. For the first time, we have been covered by thermodynamic and strucTURAL PROPERTYS ON MONOMERIC AND OLIGOMERICAL SPECIES that precede the AMILOIDE Aggregation NUCLEOS._x000D_ DURING THE FINAL PASES OF THE FINAL PROJECT OF THE FINAL PROJECT WE HAVE EXTENTED THIS METODOLOGY TO THE ANALISIS OF AB Aggregation. THE PRELIMINARY RESULTS ARE IN VERY GOOD AGREEMENT WITH THE PREDICTIONS OF OUR CINETICO MODEL. WE HAVE FOUND CONDITIONS IN WHICH THE EARLY FORMATION OF AB40 AND AB42 OLIGOMERS FROM THE MONOMERS OCCURS QUICKLY AND WITHOUT A LATENCY PHASE; The OLIGOMERS PARECEN HAVE AMILOIDE STRUCTURE, are of heterogeneous SIZE AND EVOLUCTION LENTLY FORGING PROTOFIBRILLARES PROTOFIBRILLARES AND AMILOID FIBRILLS._x000D_ ON THE BASE OF THESE RESULTS, this project is aimed at exploding more to the mechanism of the OLIGOMERISATION OF USE OF OUR METHODOLOGY WITH THE FINANCIAL RESEARCH OF THE MOLECULAR AND PHYSIC-CHIMICAL PROPIEDS OF THIS OLIGOMERICAL SPECIES AND AS EJERCES YOUR TOXIC EFFECTS IN THE CELLS. MORE SPECIFICALLY, THE MAIN OBJECTIVES ARE: TO ANALYSE QUANTITATIVELY THE CYNETIC AND THERMODYNAMIC DIFFERENCES BETWEEN AB40 AND AB42 OLIGOMERISATION, AS WELL AS OTHER VARIANTS, MIXTURES AND MUTANTS, UNDER VARIOUS EXPERIMENTAL CONDITIONS; II) CHARACTERISE THE DISTRIBUTION OF SIZES, MORPHOLOGY, STRUCTURE AND OTHER BIOPHYSIC AND THERMODYNAMIC PROPERTIES OF AB OLIGOMERS IN ORDER TO UNDERSTAND HOW THESE PROPERTIES ARE INFLUENCED BY THE FORMATION MECHANISM; To search and compare cytotoxic effects of different types of biophysicisms characterised by AB OLIGOMERS in order to establish a connection between their biophysical and their properties in the CELULAS._x000D_ to achieve these functions, we plan here a MULTIDISCIPLINAL COLABORATION focus based on our PREVIEMENT EXPERIENCE in a great variety of biophysical and biologic methods, including varietal spectroscopy, CALORIMETRIAS, RMN, ELECTRONIC MICROSCOPY AND ATOMIC FORCE, ETC. COLLECTIVELY, THE INFORMATION TO PART INFORMATION OF BIOPHIC EXPERIMENTS will provide a physicochemical BASE SOLE TO INTERPRET BY THE BIOLOGIC MECHANISMS OF AB cytotoxicity. OLIGOMEROS-INDUCED TOXICITY, CELL VIABILITY, AND MECHANISMS OF CELL DEATH IN A CELL LINE OF HUMAN NEUROBLASTOMA WILL BE EXPLORED, TRYING TO IDENTIFY THE BIOCHEMICAL PATHWAYS INVOLVED. BY MERGING ALL THIS VARIETY OF INFORMATION WE HOPE TO BROADEN THE KNOWLEDGE OF THE MOLECULAR MECHANISMS BY WHICH AB OLIGOMERS CONTRIBUTE TO THE APPEARANCE AND DEVELOPMENT OF EA. (English)
12 October 2021
0 references
Granada
0 references
Identifiers
BIO2013-40697-R
0 references