ED Sciences de la Vie et de la Santé
Alpha 1-Antitrypsin Deficiency-mediated liver disease: From the understanding of the physiopathology to the identification of biomarkers and therapeutics
by Alexandra LEHMANN (BoRdeaux Institute of onCology)
The defense will take place at 14h00 - Amphithéâtre BBS INSERM U1312 BRIC Equipe 3 Université de Bordeaux Carreire Bâtiment Bordeaux Biologie Santé - 4ème étage 2, rue du Docteur Hoffman Martinot 33000 Bordeaux
in front of the jury composed of
- Marion BOUCHECAREILH - Chargée de recherche - Université de Bordeaux - Directeur de these
- Thomas FALGUIERES - Chargé de recherche - UMR S 1193 Inserm / Université Paris-Saclay - Rapporteur
- Isabelle SERMET - Professeure des universités - praticienne hospitalière - CRMR Hôpital universitaire Necker-Enfants malades ; Service de pneumologie et d'allergologie pédiatrique ; Unité fonctionnelle mucoviscidose - Rapporteur
- Giovanni BENARD - Directeur de recherche - MALADIES RARES : GÉNÉTIQUE ET MÉTABOLISME INSERM U1211 - Examinateur
Careful control of the balance of protein homeostasis, or proteostasis, enables cells to be maintained. Homeostasis is controlled by the proteostasis network, made up of protein biogenesis, folding and degradation. All the players in this network act in concert to guarantee the integrity of proteostasis and thus ensure cellular function. On the contrary, an imbalance in proteostasis can lead to numerous pathologies such as Parkinson's, Alzheimer's, cancer or liver damage associated with Alpha 1-Antitrypsin (AAT) deficiency. To be more precise, the AAT protein is mainly produced by hepatocytes. AAT deficiency is caused by mutations in the SERPINA1 gene encoding AAT. Some of these mutations result in the production of a misfolded AAT protein, leading to its retention in the endoplasmic reticulum (ER) of hepatocytes, and consequently a defect in trafficking and secretion of the protein into the extracellular environment. Retention of misfolded proteins and their accumulation within the ER can induce hepatic proteotoxicity, leading to severe liver damage such as cirrhosis or liver cancer. However, there is considerable variability in the onset of damage in AAT deficiency, depending on severity and age of onset. In fact, only 10% of AAT-deficient patients develop severe liver damage, for which there is no treatment other than liver transplantation. This low proportion of patients developing severe liver damage suggests that other modifying factors (genetic and/or environmental) associated with mutated AAT are involved. Thus, the aim of my thesis was to identify these modifying factors in order to find new therapeutic targets and/or potential biomarkers. To meet my objective, I focused on the degradation pathway that eliminates the malformed protein: the proteasome and its specific transcription factor NRF1 (Nuclear factor erythroid 2 like 1). The proteasome is known to be responsible for degrading misfolded proteins. It has already been shown that the degradation of certain mutant AATs is slower, and the proteasome seems to be particularly to blame. I studied the status of the proteasome in two model lines of AAT deficiency (Huh7 and IB3) and was able to demonstrate that proteasome activity was not altered. However, I was able to observe an increase in messenger RNA and protein expression of certain proteasome subunits associated with overexpression/stabilization of the NRF1 protein. It is well known that this increase in NRF1 occurs following an alteration in the proteasome, in order to compensate for it. Our cell models enabled me to identify a potential alteration in the proteasome compensated for by the NRF1 protein associated with the mutant protein. These initial results led me to wonder whether the loss of NRF1 protein, whether in terms of protein expression or function, could be one of the modifying factors explaining the appearance of liver damage. To address this hypothesis, I generated non-functional NRF1 (NRF1 NF) lines suppressing its activity, and shNRF1 lines suppressing its expression. I found that the proteasome was altered and no longer compensated for by NRF1. Cell proliferation was also reduced in these lines. However, apoptosis and the cell cycle were not altered. My work during my thesis has therefore led to a better understanding of the cellular and molecular mechanisms involved in AAT deficiency associated with liver damage. This opens up new prospects for new therapeutic targets and/or biomarkers.
ED Sciences Physiques et de l'Ingénieur
Easy-to-read and inclusive school: Questions and applications of the Easy-to-read rules in elementary schools.
by Floriane BALSSA (Laboratoire de l'Intégration du Matériau au Système)
The defense will take place at 14h00 - Salle N 103 ENSC Bordeaux INP, 109 avenue Roul, 33400 Talence
in front of the jury composed of
- Véronique LESPINET-NAJIB - Maîtresse de conférences - Bordeaux INP, Laboratoire IMS - Directeur de these
- Mickaël JURY - Maître de conférences - Université Clermont Auvergne - Rapporteur
- Eric DUGAS - Professeur des universités - Université de Bordeaux - Examinateur
- Aline CHEVALIER - Professeure des universités - Université Toulouse Jean Jaurès - Rapporteur
The European Facile à Lire et à Comprendre or FALC rules aim to make information accessible to all (Inclusion Europe, 2009). In Germany (Bock et al., 2017) and Sweden (Engblom, 2019), FALC is used for language learning and to help children with reading and comprehension difficulties. In France, FALC rules are mainly used in the field of mental disabilities, and are struggling to transcend these boundaries. However, these rules could be useful to adapt texts for students with poor language skills in order to help them in understanding a text (Mazeau and Loty, 2020). This reflection is part of the inclusive school context in France, which guarantees "the inclusion in school of all children, without any distinction." (J.O July 8, 2013, article L. 111-1) and whose aim is to offer pupils physical, social and educational integration at the same time (Thomazet, 2008). However, teachers can find themselves in difficulty: lack of relevant resources, additional workload and lack of training (Lavoie et al., 2013). FALC could therefore be a relevant means of helping teachers in French elementary schools to promote the inclusion of students with special needs. Several issues emerge: Is FALC known and used by elementary school teachers? Can it be adapted to teaching issues in France? How can we encourage teachers to use FALC? In terms of literature, the aims of this thesis are as follows: 1- Examine the place of Facile à Lire et Comprendre in education. 2- To co-construct a method for applying FALC with teachers. 3- Assess the contribution of FALC rules to an inclusive school. 4- Support the integration of FALC into teachers' professional practices. To answer this question, we carried out a preliminary questionnaire survey (Balssa and Lespinet, 2022), supplemented by interviews. Analysis of the results enabled us to create personas illustrating a plurality of teachers confronted with a variety of situations, but also to identify factors that could impact on the acceptability of FALC. We have therefore defined a model for the a priori acceptability of FALC to teachers (Balssa and Lespinet, 2023). Derived from UTAUT-2 (Venkatesh et al., 2012), it allows us to consider the obstacles and levers to be taken into account when designing a FALC solution. Based on the intention to use, it is a support for adapting FALC and preparing the ground for its use, but it does not guarantee its acceptance in real-life situations or its long-term adoption (Bobillier Chaumon, 2016). Based on the principle of Research-Action-Formation (Gay and Prud'homme, 2011), two volunteer teachers experimented with FALC in their classroom. The aim was to co-construct with them a research project around FALC, adapted to their pedagogy and the needs of their students, in order to evaluate the contribution of FALC rules in the school context. The analysis of the data collected is based on evaluations carried out by the teacher, on the experience of but also on feedback from (Balssa et al., 2023b ; Balssa et al., 2024 ). This work has highlighted the value of FALC in helping students with difficulties to read, understand and, more broadly, to be included. It also highlights the need to modulate FALC so that it can be adapted to the school context. The last part of the thesis enabled us to develop the first version of a platform to support teachers in the use of FALC. It includes training videos, a guide to using the rules, and a FALC translation tool to adapt FALC to pedagogical needs.