Fatores microbianos, mecânicos e intrínsecos ao hospedeiro são os responsáveis pelo insucesso endodôntico e necessidade de reintervenção. Polimorfismos genéticos são diferenças na sequência do DNA humano que influenciam na susceptibilidade do organismo frente a doenças e nas suas respostas ao meio ambiente. O objetivo do presente estudo foi investigar o envolvimento de aspectos moleculares e clínicos na resposta do hospedeiro frente ao tratamento endodôntico, por meio da análise da expressão e frequência de polimorfismos dos genes reguladores do processo de remodelação óssea em pacientes submetidos ao tratamento endodôntico. Pacientes que apresentaram necrose pulpar e lesão periapical instalada no momento do tratamento endodôntico foram chamados para consulta de acompanhamento. Foram incluídos no presente estudo 150 pacientes, que apresentaram tratamento concluído há no mínimo um ano antes da consulta de acompanhamento. Desse total, 64 pacientes apresentaram sinais e sintomas clínicos/radiográficos indicativos de lesões periapicais persistentes, e 86 indivíduos apresentaram reparação da lesão. No momento do acompanhamento, foram coletas amostras de saliva dos pacientes como fonte de DNA genômico, o qual foi extraído a partir do pellet de células sedimentado e genotipado para RANK (rs3826620), RANKL (rs9594738) e OPG (rs2073618) por PCR em tempo real. A frequência dos genótipos e alelos foi avaliada por meio da razão de chance (odds ratio), teste do qui-quadrado ou teste exato de Fisher, utilizando os softwares Epi Info 3.5.2 e Graphpad Prism. O tempo de acompanhamento após o tratamento foi utilizado como covariável na análise de regressão logística múltipla para cada um dos polimorfismos. O nível de significância estabelecido foi de 5%. Foi observada associação na distribuição dos alelos do polimorfismo em RANK entre os grupos (p=0,04). No polimorfismo em RANKL, a distribuição dos genótipos apresentou diferença estatisticamente significante entre os grupos (p=0,05). O tempo de acompanhamento esteve associado aos casos de lesões periapicais persistentes para cada um dos polimorfismos analisados (p<0,05), sendo que na análise ajustada pelo tempo como covariável, os polimorfismos rs3826620 em RANK (p=0.02) e rs9594738 em RANKL (p=0.03) continuaram associados a lesões periapicais persistentes. O polimorfismo rs2073618 em OPG não foi associado a distribuição dos grupos em nenhuma das análises (p>0,05). Conclui-se que polimorfismos em RANK e RANKL estão associados ao risco do desenvolvimento de lesões periapicais persistentes / Microbial, mechanical and related to host response factors are responsible for endodontic failure and requirement for reintervention. Genetic polymorphisms are differences in the sequence of human DNA that influence in the susceptibility to diseases and host response to the environment. The aim of this study was to evaluate the association between molecular and clinical aspects in the host response to root canal therapy (RCT), by analyzing the expression and frequency of polymorphisms of genes regulating the bone remodeling process in patients submitted to endodontic treatment. Patients that presented pulp necrosis and apical periodontitis at the time of RCT, with at least 1 year of follow-up after RCT were recalled. Sixty-four subjects with signs/symptoms of PAP and 86 subjects with root canaltreated teeth exhibiting healthy perirradicular tissues (healed) were included. At the time of follow-up visit, saliva samples from patients were collected as a source of genomic DNA, which was extracted from the pellet of sedimented cells and used for RANK (rs3826620), RANKL (rs9594738) and OPG (rs2073618) genotyping by real-time PCR. Genotype and allele frequencies were compared by chi-square test or Fishers exact tests and odds ratio was implemented, using Epi Info 3.5.2 and Graphpad Prism. A logistic regression analysis was also performed using time of follow-up as co-variate. All tests were performed with an established alpha of 0.05. An association between allele distribution and the polymorphism in RANK was observed. Subjects that carry the allele T had a lower risk to have PAP (p=0.04). In RANKL polymorphism, the genotype distribution was statistically significant different between PAP and healed groups (p=0.05). Time of follow-up was associated with PAP (p<0.05). In the logistic regression analysis using time as a co-variant, RANK rs3826620 (p=0.02) and RANKL rs9594738 (p=0.03) were associated with PAP. The polymorphism rs2073618 in OPG was not associated with PAP (p>0.05). We conclude that polymorphisms in RANK and RANKL are associated with the risk of developing persistent periapical lesions

Le diagnostic et la prise en charge des infections ostéo-articulaires (IOA) sont souvent complexes occasionnant une perte osseuse irréversible. La variabilité intra et inter-patient en terme de présentation clinique rend impossible le recours à une description systématique ou à une analyse statistique pour le diagnostic et l'étude de cette pathologie. Le développement d'IOA résulte d'interactions complexes entre les mécanismes cellulaires et moléculaires du tissu osseux et les bactéries. L'objectif de cette thèse est de modéliser l'IOA afin de simuler le comportement du système suite à des interactions au niveau cellulaire et moléculaire en utilisant l'approche de modélisation à base d'agents. Nous avons utilisé une méthode basée sur l'analyse bibliographique pour extraire les caractéristiques du modèle et les utiliser pour deux aspects. Le premier consiste en l'élaboration de la structure du modèle en identifiant les agents et les interactions, et le deuxième concerne l'estimation quantitative des différents paramètres du modèle. La réponse du système BJI aux différentes tailles d’inoculum bactérien a été simulée par la variation de différents paramètres. L'évolution des agents simulés a ensuite été analysée en utilisant une modélisant par des systèmes dynamiques non linéaires et une méthodologie "Datadriven", grâce auxquelles nous avons décrit le système d'IOA et identifié des relations plausibles entre les agents. Le modèle a réussi à présenter la dynamique des bactéries, des cellules immunitaires innées et des cellules osseuses au cours de la première étape de l'IOA et pour différentes tailles d'inoculum bactérien. La simulation a mis en évidence les conséquences sur le tissu osseux résultant du processus de remodelage osseux au cours de l'IOA. Ces résultats peuvent être considérés comme une base pour une analyse plus approfondie et pour la proposition de différentes hypothèses et scénarios de simulation qui pourraient être étudiés dans ce laboratoire virtuel. / Bone and joint infections are one of the most challenging bone pathologies that associated with irreversible bone loss and long costly treatment. The high intra and inter patient's variability in terms of clinical presentation makes it impossible to rely on the systematic description or classical statistical analysis for its diagnosis or studying. The development of BJI encompasses a complex interplay between the cellular and molecular mechanisms of the host bone tissue and the infecting bacteria. The objective of this thesis is to provide a novel computational modeling framework that simulates the behavior resulting from the interactions on the cellular and molecular levels to explore the BJI dynamics qualitatively and comprehensively, using an agent-based modeling approach. We relied on a meta-analysis-like method to extract the quantitative and qualitative data from the literature and used it for two aspects. First, elaborating the structure of the model by identifying the agents and the interactions, and second estimating quantitatively the different parameters of the model. The BJI system’s response to different microbial inoculum sizes was simulated with respect to the variation of several critical parameters. The simulation output data was then analyzed using a data-driven methodology and system dynamics approach, through which we summarized the BJI complex system and identified plausible relationships between the agents using differential equations. The BJI model succeeded in imitating the dynamics of bacteria, the innate immune cells, and the bone cells during the first stage of BJI and for different inoculum size in a compatible way. The simulation displayed the damage in bone tissue as a result of the variation in bone remodeling process during BJI. These findings can be considered as a foundation for further analysis and for the proposition of different hypotheses and simulation scenarios that could be investigated through this BJI model as a virtual lab.