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MICE, KNOCKOUT --- PHYSIOLOGY --- MICE, KNOCKOUT --- PHYSIOLOGY

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Aims/Hypotheses. Adiponectin is an adipokine that exhibits insulin-sensitising, fat-burning and anti-inflammatory properties as well as modulatory effects on oxidative stress. We investigated the protective biological functions of ApN in skeletal muscle on ApN-knockout (KO) mice, compared to wild type mice. We hypothesized that the muscle of ApN-KO mice would undergo more serious inflammatory reactions, oxidative damage or metabolic perturbations when submitted to inflammatory stress or diabetogenic diet.
Methods. ApN-KO mice were used and compared to wild-type (WT) littermates. These two types of mice were divided in three groups. The first group was fed with a standard diet. The second one was fed with a high sucrose (HS) diabetogenic diet 6 weeks. The third group was injected with lipopolysaccharides (LPS) to induce acute inflammatory stress. At the end of the experiments, blood was sampled and tibialis anterior muscles were collected for mRNA measurements and immunochemistry.
Results. Plasma levels of free fatty acids were increased in ApN-deficient mice fed with standard or HS diet. Moreover, the HS diet led to an increase in plasma thiobarbituric acid reactive substances (TBARS), marker of systemic oxidative stress and of muscular levels of TNF-α mRNA in ApN-KO mice. Immunohistochemistry experiments showed an upregulation of peroxiredoxin-5 and caspase-6 expression in the muscle of ApN-KO mice when compared to WT littermates. These proteins are oxidative stress and apoptose markers, respectively. These abnormalities were observed in the three experimental conditions, but were more pronounced after LPS injection. Finally, in contrast to WT mice, there was an ectopic accumulation of lipids in the tibialis anterior of ApN-KO mice that was worsened following LPS injection or HS diet.
Conclusions/Interpretation. ApN deficiency led to metabolic complications and muscular injury in the mice fed with standard or HS diet or injected with LPS. These findings, more pronounced after LPS injection, suggest that ApN is a local protection to counteract the ectopic lipids storage and oxidative stress but also inflammation L’ApN est une adipocytokine ayant un rôle fondamental dans l’homéostasie énergétique et possédant à la fois des propriétés anti-inflammatoires et antioxidantes. Nous avons étudié les fonctions biologiques de l’ApN dans le muscle squelettique des souris KO-ApN comparées à des souris sauvages. Nous avons posé l’hypothèse que les muscles des souris KO-ApN devraient présenter des perturbations métaboliques ainsi qu’une réaction inflammatoire exacerbées suite à un stress inflammatoire aigu ou à un régime diabétogène.
Les souris KO-ApN sont comparées à des souris sauvages. Ces deux types de souris ont été divisés en trois groupes. Le premier groupe a reçu un régime standard. Le second a été soumis à un régime riche en sucrose (RS) durant six semaines. Enfin, le troisième groupe a été injecté au LPS (lipopolysaccharides) pour induire un stress inflammatoire aigu. A la fin de l’expérience, des échantillons de sang ont été prélevés et les muscles tibialis anterior ont té disséqués afin d’effectuer une extraction d’ARNm et des marquages immunohistochimiques.
Nos résultats montrent une augmentation des acides gras plasmatiques chez les souris KO-ApN soumises à un régime standard ou riche en sucrose. De plus, les souris KO-ApN sous régime riche en sucrose avaient des concentrations de TBARS plasmatiques et des taux d’ARNm TNF-α dans leur muscle plus élevés que les souris sauvages. A ces perturbations, s’ajoutaient au niveau des muscles, une augmentation des protéines PRDX5 et caspase-6 ainsi qu’une atteinte musculaire accompagnée d’une accumulation ectopique de lipides dans les muscles des souris KO-ApN soumises aux trois conditions expérimentales. Notons que ces observations étaient exacerbées chez les souris KO-ApN injectées au LPS.
En conclusion, l’invalidation du gène de l’ApN entraîne des complications métaboliques et une atteinte musculaire chez les souris soumises à un régime standard ou riche en sucrose ou encore injectées au LPS. Ces données, plus prononcées chez les souris injectées au LPS, suggère que l’ApN est une protection locale contre le stress oxydatif et l’accumulation ectopique de lipides mais également contre l’inflammation

Adiponectin --- Muscle, Skeletal --- Mice, Knockout

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Behavior. --- Behavioral phenotyping. --- Behavioural phenotyping. --- Knockout mouse. --- Mutant. --- Standardization. --- Transmitter.

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The problem of reverse-engineering biological networks has attracted a lot of attention in the last decades. Studying the interactions occurring inside a living organism is of great importance to understand the behavior of biological systems. The development of computer science and the abundance of new genetic data raised the question of predicting gene regulatory networks. These networks describe how some genes regulate the expression of some other genes.

Many methods have already been developed to infer these networks from gene expression data. Among them, GENIE3, a method based on Random Forests, was proposed and achieved state-of-the-art performance. However, one drawback of GENIE3 is its inability to use the specificities of some types of gene expression measurements, potentially missing useful information. In particular, datasets often include knockouts, which are measurements done after the deletion of a gene.

This thesis proposes new variants for GENIE3, based on the idea of enriched random forests, in order to integrate knockout specific information as weights guiding GENIE3 to a better prediction. First, the methods are tested on ideal cases where a knockout of every gene is available. Better predictions are indeed achieved and several ways of achieving the best results are highlighted. Realistic cases are then tested. Less convincing results are then obtained, although interesting phenomena are discovered.

The second part of the thesis studies the possibility of predicting the effect of knockouts. Differences and similarities with the GRN prediction problem are analyzed and a method of evaluation, although imperfect, is proposed. Several methods are then evaluated, showing relatively encouraging results. Some initiated reflections call for future developments.

The possibility of using the proposed weighted GENIE3 methods in other situations is also briefly explained. Important improvements are indeed achieved on several datasets without the use of knockouts.

gene regulatory network --- machine learning --- random forest --- enriched random forest --- knockout --- GRN inference --- Z-score --- Ingénierie, informatique & technologie > Sciences informatiques

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Mice, Transgenic. --- Behavior, Animal. --- Disease Models, Animal. --- Genetics, Behavioral --- Mice, Knockout. --- Phenotype. --- Neurogenetics --- Transgenic mice --- Souris transgéniques --- methods. --- Animal models --- Behavior. --- Moeurs et comportement