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BIO2009-07317

Financiado

ANALISIS TERMODINAMICO Y ESTRUCTURAL DE LA AGREGACION DE FIBRAS AMILOIDES DE PRO...

ANALISIS TERMODINAMICO Y ESTRUCTURAL DE LA AGREGACION DE FIBRAS AMILOIDES DE PROTEINAS MODELO Y RELACIONADAS CON ENFERMEDADES AMYLOID AGGREGATION OF PROTEINS IS BEHIND A VARIETY OF DISEASES OF ENORMEOUS SOCIAL AND ECONOMIC IMPACT, INCLUDING ALZHEIMER¿S AND PARKINSON¿S DISEASES, TYPE-II DIABETES AND SEVERAL ENCEPHALOPATHIES, FOR WHICH NO EFFECTIVE THERAPI... ver más

01/01/2009

UGR

218K€

Presupuesto del proyecto: 218K€

Líder del proyecto

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

Total investigadores 5509

Financiación concedida El organismo AGENCIA ESTATAL DE INVESTIGACIÓN notifico la concesión del proyecto el día 2009-01-01 No tenemos la información de la convocatoria

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UGR

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Líder del proyecto

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

Total investigadores 5509

Presupuesto del proyecto 218K€

Descripción del proyecto AMYLOID AGGREGATION OF PROTEINS IS BEHIND A VARIETY OF DISEASES OF ENORMEOUS SOCIAL AND ECONOMIC IMPACT, INCLUDING ALZHEIMER¿S AND PARKINSON¿S DISEASES, TYPE-II DIABETES AND SEVERAL ENCEPHALOPATHIES, FOR WHICH NO EFFECTIVE THERAPIES OR PREVENTION METHODS EXIST YET, THIS IS DUE TO A LACK OF A DEEP UNDERSTANDING OF THE MOLECULAR MECHANISMS OF THESE PROCESSES AND THE FACTORS TRIGGERING THEM, EVEN MORE SCARCE IS THE INFORMATION ABOUT THE ENERGETIC DETERMINANTS OF AMYLOID FIBRILLATION, WHICH IS MOTIVATED BY THE COMPLICATED NATURE OF THE AGGREGATION PROCESSES, THE DIFFICULTY IN OBTAINING HOMOGENEOUS AND REPRODUCIBLE SAMPLES OF THE AGGREGATES AND, ESPECIALLY, THE LACK OF THEORETICAL FORMALISMS TO INTERPRET THE EXPERIMENTAL DATA,THE GENERAL AIM OF THIS PROJECT IS TO CHARACTERIZE IN DETAIL THE ENERGETIC CHANGES OCCURRING DURING THE CONVERSION OF A SOLUBLE PROTEIN INTO AMYLOID FIBRILS AND TO FIND SIGNIFICANT RELATIONSHIPS BETWEEN THESE ENERGETIC PROPERTIES AND THEIR STRUCTURE AND THE MECHANISM OF FORMATION, THIS IS ESSENTIAL TO UNDERSTAND THE NATURE OF THE FORCES FAVORING THIS PROCESS,THE USE OF WELL-CHARACTERIZED MODEL PROTEINS AND PEPTIDES, EVEN UNRELATED TO DISEASE, IS A POTENT APPROACH TO INVESTIGATE AMYLOID FIBRILS AND IN FACT MUCH OF OUR ADVANCE IN THIS INTRICATE PROBLEM HAS BEEN ACHIEVED WITH MODEL SYSTEMS, DURING THE COURSE OF PREVIOUS PROJECTS, WE HAVE ADVANCED CONSIDERABLY OUR UNDERSTANDING ABOUT AMYLOID FIBRIL FORMATION BY TWO SMALL GLOBULAR PROTEINS, THE SPC-SH3 AND HYPF-N DOMAINS, SETTING A FIRM BASIS FOR THE DEVELOPMENT OF THIS PROJECT, ACCORDINGLY, WE PROPOSE A MULTIDISCIPLINARY APPROACH WITH A MAJOR PROTAGONISM OF DIFFERENTIAL SCANNING CALORIMETRY (DSC) COMBINED WITH PROTEIN ENGINEERING, HIGH-RESOLUTION NMR, HYDROGEN-DEUTERIUM (H/D) EXCHANGE METHODS AND SEVERAL SPECTROSCOPIES, TO ANALYZE AMYLOID FIBRILLATION OF SPC-SH3 AND HYPF-N,THE SPECIFIC OBJECTIVES INCLUDE FIRST TO ELUCIDATE IN DETAIL THE MECHANISM OF AMYLOID FIBRILLATION BY SPC-SH3, WITH SPECIAL FOCUS ON THE IDENTIFICATION OF EARLY INTERMEDIATES OF FIBRILLATION AND TO CHARACTERIZE THE STRUCTURE OF THESE FIBRIL PRECURSORS AT THE LEVEL OF THE RESIDUE BY NMR-DETECTED H/D EXCHANGE METHODS, THIS INFORMATION WILL BE AT THE SERVICE OF A COMPLETE INTERPRETATION OF THE THERMODYNAMIC DATA, ONCE WE HAVE A PLAUSIBLE MECHANISM OF FIBRILLATION, WE WILL ANALYZE THE THERMALLY-INDUCED FIBRILLATION AND MELTING OF PROTOFIBRILS AND FIBRILS USING DSC AND DEVELOP MATHEMATICAL FORMALISMS TO QUANTITATIVELY ANALYZE THE ENERGETICS OF THESE PROCESSES, WHICH IS THE CENTRAL OBJECTIVE OF THIS PROJECT, WE WILL TAKE BENEFIT OF THE ENERGETIC INFORMATION TO UNDERSTAND INHIBITION BY SMALL MOLECULES AND PEPTIDES OF AMYLOID FIBRILLATION, LOOKING SPECIFICALLY AT THE EFFECTS ON THE THERMODYNAMICS AND MECHANISM OF THE INHIBITION OF OLIGOMERS AND INTERMEDIATES THAT ARE THE TRUE TOXIC SPECIES TO CELLS, FINALLY, WE PLAN TO EXTEND THE METHODOLOGY DEVELOPED WITH MODEL SYSTEMS TO THE STUDY OF AMYLOID FIBRILS OF PROTEINS RELATED TO NEURODEGENERATIVE DISEASES, INCLUDING AMYLOID-BETA PEPTIDE AND ALPHA-SYNUCLEIN, WITH THE PARTICULAR AIM OF OBTAINING THERMODYNAMIC INFORMATION OF THEIR STABILITY, WHICH REMAINS LARGELY UNSTUDIED SO FAR,WE EXPECT THAT THE RESULTS OF THIS RESEARCH WILL CONTRIBUTE SIGNIFICANTLY TO INCREASE OUR UNDERSTANDING OF THE FORCES DRIVING AMYLOID AGGREGATION THAT MAY BE OF EXTRAORDINARY INTEREST IN FUTURE DEVELOPMENT OF NOVEL THERAPEUTIC OR PREVENTIVE STRATEGIES FOR NEURODEGENERATIVE DISEASES, AGREGACION\AMILOIDES\ALZHEIMER\PARKINSON\BIOFISICA\PROTEINAS\TERMODINAMICA\ESTRUCTURA

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