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Alternative splicing in type 1 diabetes
The role of the splicing factor SRSF6 in pancreatic
b-cell function and survival
Thesis submitted by Maria Inês DE OLIVEIRA ALVELOS
in fulfilment of the requirements of the PhD Degree in Biomedical and
Pharmaceutical Sciences
Thèse présentée en vue de l’obtention du titre de Docteur en Sciences
Biomédicales et Pharmaceutiques
Academic year 2020-2021
Supervisor: Professor Miriam Cnop
Co-supervisor: Professor Décio L. Eizirik
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Université Libre de Bruxelles (ULB)
Faculty of Medicine
PhD program in Biomedical and Pharmaceutical Sciences
Alternative splicing in type 1 diabetes
The role of splicing factor SRSF6 in pancreatic b-cell
function and survival
Maria Inês DE OLIVEIRA ALVELOS
in fulfilment of the requirements of the PhD Degree in Biomedical and
Pharmaceutical Sciences
Thèse présentée en vue de l’obtention du titre de Docteur en Sciences
Biomédicales et Pharmaceutiques
Members of the jury:
Professor Ingrid LANGER (President)
Professor Bernard CORVILAIN
Professor Miriam CNOP (Supervisor)
Professor Rachel DEPLUS
Professor Décio L. EIZIRIK (Co-supervisor)
Professor Marie-Isabelle GARCIA
Professor Manuel IRIMIA
Professor Arnaud ZALDUMBIDE
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TABLE OF CONTENTS
Acknowledgments ... 4
Summary ... 6
Resumé ... 8
List of abbreviations and acronyms ... 11
Publications constituting this thesis ... 16
Participation in other publications from the group ... 16
1.
INTRODUCTION ... 17
1.1 The physiology of the human pancreatic islet ... 17
1.2 How do pancreatic β-cells work? ... 18
1.3 Definition and classification of diabetes mellitus ... 21
1.4 Type 1 Diabetes (T1D) ... 23
1.4.1 Diagnosis ... 23
1.4.2 Epidemiology ... 24
1.4.3 Pathogenesis of T1D ... 24
1.4.4 Autoimmunity ... 26
1.4.5 Genetic and environmental factors leading to T1D ... 27
1.4.6 Prediction and prevention ... 31
1.5 The break of tolerance and immunopathology of T1D ... 33
1.5.1 The specificity towards the β-cells ... 34
1.6 Mechanisms of β-cell demise ... 37
1.6.1 Fas/FasL system ... 38
1.6.2 Perforin and Granzymes ... 39
1.6.3 β-cell death induced by pro-inflammatory cytokines ... 39
1.7 Another layer of complexity: the splicing process ... 44
1.7.1 Splicing regulation and the spliceosome ... 44
1.7.2 Alternative splicing ... 46
1.7.3 Splicing regulatory networks ... 52
1.7.4 Studying splicing networks using genome-wide approaches ... 54
1.7.5 The molecular mechanisms behind the regulation of alternative splicing and common features of alternative exons ... 60
1.7.6 Alternative splicing and disease ... 61
1.7.7 Alternative splicing and T1D ... 62
1.7.8 Modulation of alternative splicing ... 64
