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The Role of Cyclin D3 in Pancreatic Β-Cell Metabolic Fitness and Viability in a Cell Cycle-Independent Manner. Implications In

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The Role of Cyclin D3 in Pancreatic Β-Cell Metabolic Fitness and Viability in a Cell Cycle-Independent Manner. Implications In The role of cyclin D3 in pancreatic β-cell metabolic fitness and viability in a cell cycle-independent manner. Implications in autoimmune diabetes Noemí Alejandra Saavedra Ávila Dipòsit Legal: L.854-2014 http ://hdl.handle.net/10803/272629 ADVERTIMENT. L'accés als continguts d'aquesta tesi doctoral i la seva utilització ha de respectar els drets de la persona autora. Pot ser utilitzada per a consulta o estudi personal, així com en activitats o materials d'investigació i docència en els termes establerts a l'art. 32 del Text Refós de la Llei de Propietat Intel·lectual (RDL 1/1996). Per altres utilitzacions es requereix l'autorització prèvia i expressa de la persona autora. En qualsevol cas, en la utilització dels seus continguts caldrà indicar de forma clara el nom i cognoms de la persona autora i el títol de la tesi doctoral. No s'autoritza la seva reproducció o altres formes d'explotació efectuades amb finalitats de lucre ni la seva comunicació pública des d'un lloc aliè al servei TDX. Tampoc s'autoritza la presentació del seu contingut en una finestra o marc aliè a TDX (framing). Aquesta reserva de drets afecta tant als continguts de la tesi com als seus resums i índexs. ADVERTENCIA. El acceso a los contenidos de esta tesis doctoral y su utilización debe respetar los derechos de la persona autora. Puede ser utilizada para consulta o estudio personal, así como en actividades o materiales de investigación y docencia en los términos establecidos en el art. 32 del Texto Refundido de la Ley de Propiedad Intelectual (RDL 1/1996). Para otros usos se requiere la autorización previa y expresa de la persona autora. En cualquier caso, en la utilización de sus contenidos se deberá indicar de forma clara el nombre y apellidos de la persona autora y el título de la tesis doctoral. No se autoriza su reproducción u otras formas de explotación efectuadas con fines lucrativos ni su comunicación pública desde un sitio ajeno al servicio TDR. Tampoco se autoriza la presentación de su contenido en una ventana o marco ajeno a TDR (framing). Esta reserva de derechos afecta tanto al contenido de la tesis como a sus resúmenes e índices. WARNING. Access to the contents of this doctoral thesis and its use must respect the rights of the author. It can be used for reference or private study, as well as research and learning activities or materials in the terms established by the 32nd article of the Spanish Consolidated Copyright Act (RDL 1/1996). Express and previous authorization of the author is required for any other uses. In any case, when using its content, full name of the author and title of the thesis must be clearly indicated. Reproduction or other forms of for profit use or public communication from outside TDX service is not allowed. Presentation of its content in a window or frame external to TDX (framing) is not authorized either. These rights affect both the content of the thesis and its abstracts and indexes. i THE ROLE OF CYCLIN D3 IN PANCREATIC β-CELL METABOLIC FITNESS AND VIABILITY IN A CELL CYCLE-INDEPENDENT MANNER. IMPLICATIONS IN AUTOIMMUNE DIABETES Thesis by Noemí Alejandra Saavedra Ávila Scientific director Concepción Mora Giral In Partial Fulfillment of the Requirements for the Degree of Doctor of Biomedicine University of Lleida Lleida, Catalonia 2013 (Defended September, 2013) ii © 2013 Noemí Alejandra Saavedra Ávila All Rights Reserved iii To my parents, Erik, Ayax, Manuel and Daniel. Not only my work, but my life is yours iv v CONTENT ABSTRACT ................................................................................................................xi RESUMEN ................................................................................................................ xiii RESUM ...................................................................................................................... xv 1. Acknowledgments ........................................................................................ xvii 2. List of illustrations ......................................................................................... xix 3. Nomenclature ................................................................................................. xxi 4. Introduction ...................................................................................................... 1 7.1 Type 1 diabetes (T1D) ............................................................................................... 1 7.1.1 Genetic factors ........................................................................................................................... 2 7.1.2 Environmental factors. ............................................................................................................... 4 7.1.2.1 Climate ..................................................................................................................................... 4 7.1.2.2 Dietary factors ......................................................................................................................... 5 7.1.2.3 Viral infections ......................................................................................................................... 5 7.1.2.4 Intestinal microbiota ............................................................................................................... 6 7.1.2.5 Intestinal macrobiota: Helminths .......................................................................................... 6 7.1.3 Pathogenesis of T1DM .............................................................................................................. 7 7.2 β‐cell function ........................................................................................................... 11 7.2.3 Regulation of β-cell function ................................................................................................... 15 7.2.4 Metabolic factors and glucose-stimulated insulin secretion ............................................... 16 7.2.4.1 Mitochondrial signalling........................................................................................................ 16 vi 7.2.4.2 Calcium signalling and CaMKII .......................................................................................... 18 7.2.4.3 The G-protein coupled signalling pathways: PKA and PKC .......................................... 18 7.2.4.4 The cGMP/PKG pathway .................................................................................................... 20 7.2.4.5 Other factors that can modulate insulin secretion ........................................................... 20 7.3 Cell cycle ................................................................................................................... 24 7.3.1 The family of cyclin proteins .................................................................................................. 24 7.3.1.1 D-type Cyclins ..................................................................................................................... 25 7.3.1.1.1 CDK activation .................................................................................................................. 25 7.3.1.1.2 Non-catalytic functions. .................................................................................................... 27 7.3.1.2 D-type cyclins and β pancreatic cells ............................................................................... 30 7.3.1.1.2 Cell cycle proteins in glucose metabolism .................................................................... 30 7.3.1.1.2.1 Cyclins ............................................................................................................................ 31 7.3.1.1.2.2 CDKs ............................................................................................................................... 32 7.3.1.1.2.3 E2F1 ................................................................................................................................ 33 7.3.1.1.2.4 Inhibitors ......................................................................................................................... 33 7.3.1.1.3 Cyclin D3 ............................................................................................................................ 34 8. Rationale and hypothesis ............................................................................. 38 9. Objectives ........................................................................................................ 42 9.1 Main goal ............................................................................................................ 42 9.2 Specific goals .................................................................................................... 42 10. Materials and methods ............................................................................... 46 10.1 Mice ..................................................................................................................... 46 10.2 Generation of the NOD/CcnD3 KO mice. ........................................................... 47 vii 10.3 Generation of the NOD/RIPCcnD3 transgenic mice. ........................................ 47 10.4 Generation of NODCcnD3KO/RIP CcnD3 mice. ................................................ 48 10.5 Generation of the different NOD/SCID strains .................................................. 48 10.5.1 Genotyping of the SCID mutation in the different NOD strains. ...................................... 48 10.6 Assessment
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