Reprogrammation comportementale : modèles, algorithmes et application aux maladies complexes

Abstract : Complex diseases such as cancer and Alzheimer’s are caused by multiple molecular perturbations responsible for pathological cellular behavior. A major challenge of precision medicine is the identification of the molecular perturbations induced by the diseases and the therapies from their consequences on cell phenotypes. We define a model of complex diseases, called behavioral reprogramming, that assimilates the molecular perturbations to alterations of the dynamic local functions of discrete dynamical systems inducing a reprogramming of the global dynamics of the network. This modeling framework relies on the one hand, on Control Boolean networks, which are Boolean networks containing control parameters modeling the perturbations and, on the other hand, the definition of reprogramming modes (Possibility, Necessity) expressing the objective of the behavioral reprogramming. Fromthis framework, we prove that the computation of the cores, namely, the minimal sets of action enabling reprogramming is a problem of abductive inference in propositional logic.Using historical methods computing the prime implicants of Boolean functions, we develop two methods computing all the reprogramming cores. Finally, we evaluate the modeling framework for the identification of perturbations responsible for the transformation of a healthy cell into a cancer cell and the discovery of therapeutic targets on a model of breast cancer. In particular, we show that the perturbations inferred by our methods are compatible with biological knowledge by discriminating oncogenes and tumor suppressor genes and by recovering the causal of the BRCA1 gene. In addition, themethod recovers the synthetic lethality phenomenon between PARP1 and BRCA1 that constitutes an optimal anti-cancer treatment because it specifically targets tumor cells.
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Célia Biane. Reprogrammation comportementale : modèles, algorithmes et application aux maladies complexes. Logique en informatique [cs.LO]. Université Paris-Saclay; Université d'Evry-Val-d'Essonne, 2018. Français. ⟨NNT : 2018SACLE050⟩. ⟨tel-02107110⟩

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