DYNAMICS OF MEMBRANE ARCHITECTURE. MOLECULAR INTERACTIONS AND APPLICATION IN AUTOPHAGIA (Q3142569): Difference between revisions
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DYNAMIQUE DE L’ARCHITECTURE MEMBRANAIRE. INTERACTIONS MOLÉCULAIRES ET APPLICATION EN AUTOPHAGIE | |||
Revision as of 12:47, 2 December 2021
Project Q3142569 in Spain
| Language | Label | Description | Also known as |
|---|---|---|---|
| English | DYNAMICS OF MEMBRANE ARCHITECTURE. MOLECULAR INTERACTIONS AND APPLICATION IN AUTOPHAGIA |
Project Q3142569 in Spain |
Statements
100,793.0 Euro
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201,586.0 Euro
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50.0 percent
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1 January 2016
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31 December 2019
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UNIVERSIDAD DEL PAIS VASCO/EUSKAL HERRIKO UNIBERTSITATEA
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43°19'37.56"N, 2°59'4.60"W
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48054
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LAS MEMBRANAS CELULARES ESTAN CONSTITUIDAS POR UNA DOBLE CAPA DE FOSFOLIPIDOS, A LA CUAL SE ASOCIAN PROTEINAS CON DIFERENTES NIVELES DE INTERACCION Y COMPLEJIDAD. EL ELEMENTO BASICO EN LA ARQUITECTURA DE LA MEMBRANA ES EL INTERIOR HIDROFOBICO DE LA BICAPA LIPIDICA. ASI, LAS MUCHAS REACCIONES BIOQUIMICAS QUE TIENEN LUGAR EN LA MEMBRANA SE PRODUCEN EN UNA ESTRUCTURA BIDIMENSIONAL LIQUIDO-CRISTALINA. LAS INTERACCIONES MOLECULARES EN ESTE ENTORNO TAN PECULIAR SON MUY COMPLEJAS Y DIFICILES DE ESTUDIAR. LA DIFICULTAD AUMENTA POR EL HECHO DE QUE LA ARQUITECTURA DE LA MEMBRANA NO ES ESTATICA, SINO QUE VARIA CONSTANTEMENTE CON EL TIEMPO Y EN EL PLANO DE LA MEMBRANA. LAS HETEROGENEIDADES OBSERVADAS EN EL PLANO SE LLAMAN NORMALMENTE ¿DOMINIOS DE MEMBRANA¿. LOS ESFINGOLIPIDOS SON UNA CLASE POCO ABUNDANTE DE LIPIDOS, QUE A MENUDO DAN ORIGEN A DOMINIOS DE MEMBRANA ESPECIALIZADOS. EN NUESTRO LABORATORIO SE HAN ESTUDIADO CON DETALLE LAS PROPIEDADES BIOFISICAS DE ESTOS LIPIDOS (SOBRE TODO CERAMIDAS) Y DOMINIOS, Y LOS ESTUDIOS CONTINUARAN A LO LARGO DE ESTE PROYECTO. A LA VEZ, OTROS ESTUDIOS DE NUESTRO GRUPO SE HAN DIRIGIDO A LA AUTOFAGIA, UN PROCESO INTRACELULAR DE DEGRADACION DE MACROMOLECULAS Y ORGANULOS QUE ES ESENCIAL PARA LA HOMEOSTASIS DE CELULAS Y TEJIDOS, Y QUE ESTA RELACIONADO CON ENFERMEDADES IMPORTANTES. LA AUTOFAGIA COMIENZA POR LA FORMACION DE UNA MEMBRANA DE AISLAMIENTO, O FAGOFORO, QUE SECUESTRA LA CARGA A DEGRADAR ANTES DE CERRARSE SOBRE SI MISMO, FORMANDO EL AUTOFAGOSOMA. ESTE SE FUSIONA LUEGO CON LOS LISOSOMAS PARA DEGRADAR SU CARGA. NO SE CONOCE BIEN COMO SE FORMA Y SE ALARGA EL AUTOFAGOSOMA. SE HAN IDENTIFICADO EN MAMIFEROS UNAS 20 PROTEINAS ATG (AUTOPHAGY-RELATED). EL OBJETIVO PRINCIPAL DE ESTE PROYECTO ES RECONSTITUIR EN SISTEMAS FUNCIONALES MINIMOS, A PARTIR DE LIPIDOS PUROS Y PROTEINAS ATG HUMANAS, EL FENOMENO DE FORMACION Y ALARGAMIENTO DEL AUTOFAGOSOMA, CON EL FIN DE OBTENER UNA COMPRENSION MECANISTICA DETALLADA DEL PROCESO A NIVEL MOLECULAR. SE ESTUDIARAN DOS SISTEMAS MULTIPROTEICOS, QUE GUARDAN SEMEJANZA CON LA CASCADA DE UBIQUITINACION DE PROTEINAS, A SABER LOS LLAMDSO SISTEMAS ATG8 Y ATG12, Y TAMBIEN SE ESTUDIARA LA IMPORTANTE PROTEINA INTRINSECA DE MEMBRANA ATG9. SE CARACTERIZARA UN AMPLIO ESPECTRO DE LAS INTERACCIONES MOLECULARES QUE ENTRELAZAN LOS COMPONENTES MENCIONADOS, UTILIZANDO TECNICAS BIOFISICAS AVANZADAS, COMO LA ESPECTROSCOPIA DE CORRELACION DE FLUORESCENCIA, LAS MICROSCOPIAS CONFOCAL Y DE FUERZA ATOMICA, LA MICROSCOPIA CRIO-ELECTRONICA, Y EL ANALISIS LIPIDOMICO. POR OTRA PARTE SE SABE QUE LAS CERAMIDAS, UNA IMPORTANTE CLASE DE ESFINGOLIPIDOS, PUEDEN MODULAR LA AUTOFAGIA, A TRAVES DE MECANISMOS MAL CONOCIDOS. SE LLEVARAN A CABO EXPERIMENTOS DESTINADOS A PROBAR LA HIPOTESIS SEGUN LA CUAL LAS CERAMIDAS REGULAN LA AUTOFAGIA, AL MENOS EN PARTE, A TRAVES DE CAMBIOS EN LA ARQUITECTURA MOLECULAR DE LAS MEMBRANAS. (Spanish)
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THE CELL MEMBRANES ARE FORMED BY A DOUBLE LAYER OF PHOSPHOLIPIDS, TO WHICH PROTEINS ARE ASSOCIATED WITH DIFFERENT LEVELS OF INTERACTION AND COMPLEXITY. THE BASIC ELEMENT IN MEMBRANE ARCHITECTURE IS THE HYDROPHOBIC INTERIOR OF THE LIPID BILAYER. THUS, THE MANY BIOCHEMICAL REACTIONS THAT OCCUR IN THE MEMBRANE OCCUR IN A TWO-DIMENSIONAL LIQUID-CRYSTALLINE STRUCTURE. MOLECULAR INTERACTIONS IN THIS PECULIAR ENVIRONMENT ARE VERY COMPLEX AND DIFFICULT TO STUDY. THE DIFFICULTY IS INCREASED BY THE FACT THAT THE MEMBRANE ARCHITECTURE IS NOT STATIC, BUT VARIES CONSTANTLY OVER TIME AND IN THE PLANE OF THE MEMBRANE. THE HETEROGENEITIES OBSERVED IN THE PLANE ARE USUALLY CALLED MEMBRANE DOMAINS. ESFINGOLIPIDS ARE AN INFREQUENT CLASS OF LIPIDS, WHICH OFTEN GIVE RISE TO SPECIALISED MEMBRANE DOMAINS. IN OUR LABORATORY WE HAVE STUDIED IN DETAIL THE BIOPHYSIC PROPERTIES OF THESE LIPIDS (ESPECIALLY CERAMIDES) AND DOMAINS, AND THE STUDIES WILL CONTINUE THROUGHOUT THIS PROJECT. AT THE SAME TIME, OTHER STUDIES OF OUR GROUP HAVE FOCUSED ON AUTOPHAGIA, AN INTRACELLULAR PROCESS OF DEGRADATION OF MACROMOLECULES AND ORGANULOS THAT IS ESSENTIAL FOR THE HOMEOSTASIS OF CELLS AND TISSUES, AND THAT IS RELATED TO IMPORTANT DISEASES. AUTOPHAGIA BEGINS WITH THE FORMATION OF AN ISOLATION MEMBRANE, OR FAGOFORO, WHICH ABDUCTS THE LOAD TO DEGRADE BEFORE CLOSING OVER ITSELF, FORMING THE AUTOPHAGOSOMA. IT THEN MERGES WITH THE LYSOSOMES TO DEGRADE ITS LOAD. IT IS NOT WELL KNOWN HOW IT FORMS AND THE AUTOPHAGOSOMA IS EXTENDED. ABOUT 20 ATG PROTEINS (AUTOPHAGY-RELATED) HAVE BEEN IDENTIFIED IN MAMMALS. THE MAIN OBJECTIVE OF THIS PROJECT IS TO RECONSTITUTE IN MINIMAL FUNCTIONAL SYSTEMS, FROM PURE LIPIDS AND HUMAN ATG PROTEINS, THE FORMATION AND ELONGATION PHENOMENE OF THE AUTOPHAGOSOMA, IN ORDER TO OBTAIN A DETAILED MECHANITIC UNDERSTANDING OF THE PROCESS AT THE MOLECULAR LEVEL. TWO MULTIPROTEIN SYSTEMS, WHICH RESEMBLE THE CASCADE OF PROTEIN UBIQUITINATION, NAMELY THE LLAMDSO SYSTEMS ATG8 AND ATG12, WILL BE STUDIED, AND THE IMPORTANT INTRINSIC PROTEIN OF ATG9 MEMBRANE WILL ALSO BE STUDIED. A BROAD SPECTRUM OF MOLECULAR INTERACTIONS THAT INTERTWINE THE AFOREMENTIONED COMPONENTS WILL BE CHARACTERISED, USING ADVANCED BIOPHYSIC TECHNIQUES, SUCH AS FLUORESCENCE CORRELATION SPECTROSCOPY, CONFOCAL AND ATOMIC STRENGTH MICROSCOPY, CRYO-ELECTRONIC MICROSCOPY, AND LIPIDOMIC ANALYSIS. ON THE OTHER HAND IT IS KNOWN THAT CERAMIDES, AN IMPORTANT CLASS OF ESFINGOLIDIDS, CAN MODULATE AUTOPHAGIA, THROUGH POORLY KNOWN MECHANISMS. EXPERIMENTS WILL BE CARRIED OUT TO TEST THE HYPOTHESES ACCORDING TO WHICH CERAMIDES REGULATE AUTOPHAGIA, AT LEAST IN PART, THROUGH CHANGES IN THE MOLECULAR ARCHITECTURE OF THE MEMBRANES. (English)
12 October 2021
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Leioa
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Identifiers
BFU2015-66306-P
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