The severity of cardiac dysfunction predicts mortality in septic patients. In this thesis, I have investigated the pathophysiology and the novel therapeutic strategy to attenuate cardiac dysfunction in experimental sepsis. I have developed a model of cardiac dysfunction caused by lipopolysaccharide (LPS)/peptidoglycan (PepG) co-administration or polymicrobial sepsis in young and old, male and female mice. There is good evidence that females tolerate sepsis better than males. Here, I have demonstrated for the first time that the cardiac dysfunction caused by sepsis was less pronounced in female than in male mice; this protection was associated with cardiac activation of a pro-survival pathway [Akt and endothelial nitric oxide synthase], and the decreased activation of a pro-inflammatory signalling pathway [nuclear factor (NF)-κB]. Patients with chronic kidney disease (CKD) requiring dialysis have a higher risk of sepsis and a 100-fold higher mortality. Activation of NF-κB is associated with sepsis-induced cardiac dysfunction and NF-κB is activated by IκB kinase (IKK). Here, I have shown that 5/6th nephrectomy for 8 weeks caused a small, but significant, cardiomyopathy, cardiac activation of NF-κB and expression of inducible nitric oxide synthase (iNOS). When subjected to LPS or polymicrobial sepsis, CKD mice exhibited exacerbation of cardiac dysfunction and cardiac activation of NF-κB and iNOS expression, which were attenuated by a specific IKK inhibitor (IKK 16). Thus, selective inhibition of IKK may represent a novel therapeutic approach for the sepsis-induced cardiac dysfunction in CKD patients. Activation of transient receptor potential vanilloid receptor type 1 (TRPV1) improves outcome in sepsis/endotoxaemia. The identity of the endogenous activators of TRPV1 and the role of the channel in the cardiac dysfunction caused by sepsis/endotoxaemia is unknown. Here, I have shown that activation of TRPV1 by 12-(S)-HpETE and 20-HETE (potent ligands of TRPV1) leads to the release of calcitonin gene-related peptide (downstream mediator of TRPV1 activation), which protects the heart against the cardiac dysfunction caused by LPS.

Our society has become less physically active (U.S. Department of Health and Human Services, 2010) and less connected to nature than ever before (Berger & Mcleod, 2006). Spending leisure time indoors, technological advancements, urban living, and car dependent communities have led to these changes (Dustin, Bricker, & Schwab, 2010; Hansen-Ketchum, Marck, & Reutter, 2009; Norman & Mills, 2004). As a result, physical health and mental health is deteriorating (Dustin et al., 2010; Maller, Townsend, Pryor, Brown & Leger, 2005). Physical activity and nature can each produce mental and physical health benefits; some approaches such as adventure-based counseling and wilderness therapy already incorporate these elements. A promising alternative approach using physical activity and nature has received attention in recent years. Walk and talk therapy has been described as an intervention that combines counseling, walking, and the outdoors (Doucette, 2004). Despite, a small number of therapists using the approach (Gontang, 2009), anecdotal research (Hays, 1994), and a description of the approach (Doucette, 2004), little is known about walk and talk therapy. In this qualitative study 11 therapists were interviewed about their experiences with walk and talk therapy. Main themes of the study suggested characteristics, a procedure, reasons walk and talk therapy evolved, limitations, outcomes, and a framework for practice for walk and talk therapy. Therapists believe walk and talk therapy is beneficial for clients as well as therapists. Implications for therapists, researchers, and counselor educators are provided.

Dans les années 20, Otto Warburg émit l’hypothèse que l’altération des mitochondries est la cause du développement du cancer bien qu’il reconnaissait l’existence de tumeurs oxydatives. Egalement, Weinhouse (1950) parmi d’autres, a établi qu’une respiration mitochondriale défectueuse n’était pas une caractéristique systématique du cancer et Peter Vaupel a suggéré dans les années 90 que l’oxygénation de la tumeur était le facteur limitant de la production énergétique de la mitochondrie dans le cancer plutôt que la capacité mitochondriale elle-même. Cette thèse ainsi que des études récentes montrent clairement que les mitochondries sont fonctionnelles dans les tumeurs et la discipline d’oncobioénergétique a identifié Myc, Src, Oct1 et Ras comme des oncogènes pro-OXPHOS. De plus, l’adaptation des cellules cancéreuses à l’aglycémie, la symbiose métabolique entre les régions hypoxiques et normoxiques des tumeurs ainsi que l’hypothèse de Reverse Warburg effect supportent le rôle crucial des mitochondries dans la survie d’un groupe de tumeurs. Par conséquent, les mitochondries sont maintenant considérées come des cibles potentielles pour la thérapie anti-cancéreuse et des tentatives incluant la modulation bioénergétique pourraient être considéré pour tuer les cellules cancéreuses. Nous montrons l’effet anti-cancéreux de deux modulateurs mitochondriaux et disséquons leur mécanisme d’action. / In the 1920s, Otto Warburg first hypothesized that mitochondrial impairment is a leading cause of cancer although he recognized the existence of oxidative tumors. Likewise, Weinhouse (1950) and others found that deficient mitochondrial respiration is not an obligatory feature of cancer and Peter Vaupel suggested in the 90s that tumor oxygenation rather than OXPHOS capacity was the limiting factor of mitochondrial energy production in cancer. This thesis and recent studies now clearly indicate that mitochondria are highly functional in tumors and the field of oncobioenergetic identified Myc, Src, Oct1 and RAS as pro-OXPHOS oncogenes. In addition, cancer cells adaptation to aglycemia, metabolic symbiosis between hypoxic and non-hypoxic tumor regions as well the reverse Warburg hypothesis support the crucial role of mitochondria in the survival of a subclass of tumors. Therefore, mitochondria are now considered as potential targets for anti-cancer therapy and tentative strategies including a bioenergetic profile characterization of the tumor and the subsequent adapted bioenergetic modulation could be considered for cancer killing. We show anti-cancer effects of two mitochondrial modulators and dissect their mechanism of action.

Introdução: a transmissão ocupacional do HIV, HBV e HCV aos profissionais da área da saúde é um fato concreto. Objetivos: avaliar a conduta dos profissionais de enfermagem vítimas de acidentes com material biológico de um hospital de ensino do interior paulista em relação ao atendimento e seguimento clínico especializado. Material e método: trata-se de um estudo de corte transversal aprovado pelos Comitês de Ética em Pesquisa do referido hospital e da Escola de Enfermagem de Ribeirão Preto da Universidade de São Paulo. A população do estudo foi composta por 1.215 profissionais de enfermagem, que foram entrevistados no período de 01 de junho de 2010 a 30 de maio de 2011. Resultados: dos 1.215 profissionais da equipe de enfermagem entrevistados, 636 (52,3%) sofreram pelo menos um acidente com material biológico ao longo de sua experiência profissional, 454 (71,4%) procuraram pelo atendimento especializado no Ambulatório de Acidente Ocupacional ao Profissional da Saúde (AOPS) e 26 (5,7%) interromperam o seguimento clínico antes do período recomendado e os motivos mais frequentemente relatados foram atendimento demorado (26,9%), sorologia do paciente fonte negativa (23,1%) e (15,4%) esquecimento. 168 (37,0%) profissionais acidentados tiveram indicação de antirretrovirais, sendo que 109 (64,9%) tiveram efeitos adversos e 52 (31,0%) abandonaram a terapêutica. Apresentar efeitos adversos foi o motivo mais frequentemente relatado para interrupção dos antirretrovirais (94,3%). Ressalta-se que 182 profissionais acidentados não procuraram atendimento no AOPS e a maioria 115 (63,2%) relatou não tê-lo procurado, pois acreditavam que o acidente era de baixo risco. Conclusão: identificar os motivos que levam os profissionais a não procurar atendimento, bem como completar a terapêutica e o seguimento clínico pode contribuir para a proposição de estratégias capazes de aumentar a adesão dos profissionais às medidas profiláticas após exposição ocupacional a material biológico, e consequentemente minimizar o risco de soroconversão ao HIV e HBV e identificar precocemente a soroconversão para o HCV, uma vez que não existe, até o momento, quimioprofilaxia para minimizar o risco de soroconversão para este vírus. / Introduction: occupational transmission of HIV, HBV and HCV to health professionals is a concrete fact. Objectives: to evaluate the conduct of nursing professionals from a teaching hospital in the interior of the state of São Paulo, Brazil, who were victims of accidents with biological material in relation to the care and specialized clinical follow-up. Material and method: it is a cross-sectional study which was approved by the Research Ethics Committees of the studied Hospital and of the Ribeirão Preto College of Nursing, University of São Paulo. The study population consisted of 1,215 nursing professionals, who were interviewed in the period from June, 1st 2010 to May, 30rd 2011. Results: of the 1,215 nursing professionals interviewed, 636 (52.3%) have experienced at least one accident with biological material throughout their professional experience, 454 (71.4%) sought specialized care at the Outpatient Clinic for Occupational Accident among Health Care Workers (AOPS) and 26 (5.7%) discontinued the clinical follow-up before the recommended period, and the reasons most frequently reported were delayed care (26.9%), patients with negative serology (23.1%) and forgetfulness (15.4%). 168 injured professionals (37.0%) had an indication for antiretroviral therapy, being that 109 (64.9%) of them had adverse effects and 52 (31.0%) abandoned therapy. Having adverse effects was the most frequently reported reason for discontinuation of antiretrovirals (94.3%). It is highlighted that 182 injured professionals did not seek care at the AOPS and the majority, i.e. 115 (63.2%) professionals, reported not seeking it, because they believed that the accident was at low risk. Conclusion: identifying the reasons why professionals do not seek care and not complete the treatment and the clinical follow-up may contribute to the proposition of strategies to increase professionals\' adherence to the prophylaxis measures after occupational exposure to biological material, and therefore minimize the risk of seroconversion to HIV and HBV, and identify early HCV seroconversion, since there is not, so far, chemoprophylaxis to minimize the risk of seroconversion to this virus.

Introdução: Os profissionais de enfermagem são os que mantêm os maiores índices de acidentes com material biológico. A importância da adoção de medidas preventivas é fundamental para garantir a proteção dos mesmos e reduzir os acidentes de trabalho. Após a ocorrência de um acidente ocupacional com material biológico, medidas pós-exposições devem ser instituídas para reduzir o risco de soroconversão. Objetivo: Analisar as condutas referidas pelos profissionais de enfermagem após a ocorrência de exposição ocupacional percutânea com material biológico potencialmente contaminado. Material e Método: Trata-se de estudo do tipo transversal, realizado em um hospital de alta complexidade, localizado no interior do Estado de São Paulo, Brasil. O projeto foi aprovado pelo Comitê de Ética em Pesquisa da instituição e da Escola de Enfermagem de Ribeirão Preto da Universidade de São Paulo. A amostra do estudo foi composta por profissionais de enfermagem. Os dados foram coletados por meio de entrevistas individuais no próprio local de trabalho, no período entre março e novembro de 2015. Resultado: Foram entrevistados 226 profissionais; desses, 39 (17,3%) afirmaram ter sofrido exposição ocupacional a material biológico na instituição, sendo que a maioria 24 (61,5%) envolveu contato por via percutânea. Em relação às condutas referidas pelos profissionais de enfermagem após exposição ocupacional com material biológico potencialmente contaminado, a maior parte dos participantes: interromperam imediatamente a atividade que estavam fazendo (87,5%), lavaram a área atingida abundantemente com água e sabão (100,0%), realizaram o comunicado imediato ao enfermeiro supervisor sobre o acidente (95,8%), preencheram o formulário para investigação de acidentes e foram encaminhados para o atendimento especializado (95,8%). Os profissionais mencionaram a emissão da Comunicação de Acidente de Trabalho pelo Serviço de Engenharia de Segurança e Medicina do Trabalho em 100,0% dos casos de acidentes com material biológico. Conclusão: O presente estudo permitiu identificar as condutas referidas pelos profissionais de enfermagem após exposição ocupacional com material biológico potencialmente contaminado. Destaca-se que a maioria interrompeu a atividade desenvolvida no momento do acidente, realizou cuidados na área atingida, procurou imediatamente pelo enfermeiro supervisor, atendimento clínico especializado e notificou o acidente / Introduction: Nursing professionals have the highest rates of accidents with biological material. The importance of adopting preventive measures is fundamental to ensure their protection and reduce work accidents. After the occurrence of an occupational accident with biological material, post-exposure measures must be followed to reduce the risk of seroconversion. Objective: To analyze the approaches mentioned by nursing professionals after the occurrence of a percutaneous occupational accident with potentially contaminated biological material. Material and Method: A cross-sectional study was conducted in a high-complexity hospital in the interior of the state of São Paulo, Brazil. The research project was approved by the Research Ethics Committee of the institution and the Ribeirão Preto College of Nursing, at the University of São Paulo. The study sample was made up of nursing professionals. Data were collected by means of individual interviews at the participants\' workplace, between March and November 2015. Result: A total of 226 professionals were interviewed; of these, 39 (17.3%) stated they had suffered occupational exposure to biological material at the institution, of whom 24 (61.5%) involved percutaneous contact. Regarding the therapeutic approaches mentioned by the nursing professionals after the occupational exposure to potentially contaminated biological material, most participants interrupted the activity they were doing immediately (87.5%), washed the affected area abundantly with water and soap (100,0%), immediately reported the accident to the supervisor nurse (95.8%), filled in a form for investigation of accidents and were referred to specialized care (95.8%). It is noteworthy that the professionals mentioned the issuance of the Work Accident Notification to the Work Medicine and Safety Engineering Service in 100,0% of the cases of accidents with biological material. Conclusion: The present study allowed to identify the approaches mentioned by nursing professionals after occupational exposure to potentially contaminated biological material. It is noteworthy that most professionals interrupted the activity they were developing at the time of the accident, cared for the affected area, sought the supervisor nurse immediately, as well as specialized clinical care, and notified the accident

Introdução: Os profissionais de enfermagem são os que mantêm os maiores índices de acidentes com material biológico. A importância da adoção de medidas preventivas é fundamental para garantir a proteção dos mesmos e reduzir os acidentes de trabalho. Após a ocorrência de um acidente ocupacional com material biológico, medidas pós-exposições devem ser instituídas para reduzir o risco de soroconversão. Objetivo: Analisar as condutas referidas pelos profissionais de enfermagem após a ocorrência de exposição ocupacional percutânea com material biológico potencialmente contaminado. Material e Método: Trata-se de estudo do tipo transversal, realizado em um hospital de alta complexidade, localizado no interior do Estado de São Paulo, Brasil. O projeto foi aprovado pelo Comitê de Ética em Pesquisa da instituição e da Escola de Enfermagem de Ribeirão Preto da Universidade de São Paulo. A amostra do estudo foi composta por profissionais de enfermagem. Os dados foram coletados por meio de entrevistas individuais no próprio local de trabalho, no período entre março e novembro de 2015. Resultado: Foram entrevistados 226 profissionais; desses, 39 (17,3%) afirmaram ter sofrido exposição ocupacional a material biológico na instituição, sendo que a maioria 24 (61,5%) envolveu contato por via percutânea. Em relação às condutas referidas pelos profissionais de enfermagem após exposição ocupacional com material biológico potencialmente contaminado, a maior parte dos participantes: interromperam imediatamente a atividade que estavam fazendo (87,5%), lavaram a área atingida abundantemente com água e sabão (100,0%), realizaram o comunicado imediato ao enfermeiro supervisor sobre o acidente (95,8%), preencheram o formulário para investigação de acidentes e foram encaminhados para o atendimento especializado (95,8%). Os profissionais mencionaram a emissão da Comunicação de Acidente de Trabalho pelo Serviço de Engenharia de Segurança e Medicina do Trabalho em 100,0% dos casos de acidentes com material biológico. Conclusão: O presente estudo permitiu identificar as condutas referidas pelos profissionais de enfermagem após exposição ocupacional com material biológico potencialmente contaminado. Destaca-se que a maioria interrompeu a atividade desenvolvida no momento do acidente, realizou cuidados na área atingida, procurou imediatamente pelo enfermeiro supervisor, atendimento clínico especializado e notificou o acidente / Introduction: Nursing professionals have the highest rates of accidents with biological material. The importance of adopting preventive measures is fundamental to ensure their protection and reduce work accidents. After the occurrence of an occupational accident with biological material, post-exposure measures must be followed to reduce the risk of seroconversion. Objective: To analyze the approaches mentioned by nursing professionals after the occurrence of a percutaneous occupational accident with potentially contaminated biological material. Material and Method: A cross-sectional study was conducted in a high-complexity hospital in the interior of the state of São Paulo, Brazil. The research project was approved by the Research Ethics Committee of the institution and the Ribeirão Preto College of Nursing, at the University of São Paulo. The study sample was made up of nursing professionals. Data were collected by means of individual interviews at the participants\' workplace, between March and November 2015. Result: A total of 226 professionals were interviewed; of these, 39 (17.3%) stated they had suffered occupational exposure to biological material at the institution, of whom 24 (61.5%) involved percutaneous contact. Regarding the therapeutic approaches mentioned by the nursing professionals after the occupational exposure to potentially contaminated biological material, most participants interrupted the activity they were doing immediately (87.5%), washed the affected area abundantly with water and soap (100,0%), immediately reported the accident to the supervisor nurse (95.8%), filled in a form for investigation of accidents and were referred to specialized care (95.8%). It is noteworthy that the professionals mentioned the issuance of the Work Accident Notification to the Work Medicine and Safety Engineering Service in 100,0% of the cases of accidents with biological material. Conclusion: The present study allowed to identify the approaches mentioned by nursing professionals after occupational exposure to potentially contaminated biological material. It is noteworthy that most professionals interrupted the activity they were developing at the time of the accident, cared for the affected area, sought the supervisor nurse immediately, as well as specialized clinical care, and notified the accident

Introdução: a transmissão ocupacional do HIV, HBV e HCV aos profissionais da área da saúde é um fato concreto. Objetivos: avaliar a conduta dos profissionais de enfermagem vítimas de acidentes com material biológico de um hospital de ensino do interior paulista em relação ao atendimento e seguimento clínico especializado. Material e método: trata-se de um estudo de corte transversal aprovado pelos Comitês de Ética em Pesquisa do referido hospital e da Escola de Enfermagem de Ribeirão Preto da Universidade de São Paulo. A população do estudo foi composta por 1.215 profissionais de enfermagem, que foram entrevistados no período de 01 de junho de 2010 a 30 de maio de 2011. Resultados: dos 1.215 profissionais da equipe de enfermagem entrevistados, 636 (52,3%) sofreram pelo menos um acidente com material biológico ao longo de sua experiência profissional, 454 (71,4%) procuraram pelo atendimento especializado no Ambulatório de Acidente Ocupacional ao Profissional da Saúde (AOPS) e 26 (5,7%) interromperam o seguimento clínico antes do período recomendado e os motivos mais frequentemente relatados foram atendimento demorado (26,9%), sorologia do paciente fonte negativa (23,1%) e (15,4%) esquecimento. 168 (37,0%) profissionais acidentados tiveram indicação de antirretrovirais, sendo que 109 (64,9%) tiveram efeitos adversos e 52 (31,0%) abandonaram a terapêutica. Apresentar efeitos adversos foi o motivo mais frequentemente relatado para interrupção dos antirretrovirais (94,3%). Ressalta-se que 182 profissionais acidentados não procuraram atendimento no AOPS e a maioria 115 (63,2%) relatou não tê-lo procurado, pois acreditavam que o acidente era de baixo risco. Conclusão: identificar os motivos que levam os profissionais a não procurar atendimento, bem como completar a terapêutica e o seguimento clínico pode contribuir para a proposição de estratégias capazes de aumentar a adesão dos profissionais às medidas profiláticas após exposição ocupacional a material biológico, e consequentemente minimizar o risco de soroconversão ao HIV e HBV e identificar precocemente a soroconversão para o HCV, uma vez que não existe, até o momento, quimioprofilaxia para minimizar o risco de soroconversão para este vírus. / Introduction: occupational transmission of HIV, HBV and HCV to health professionals is a concrete fact. Objectives: to evaluate the conduct of nursing professionals from a teaching hospital in the interior of the state of São Paulo, Brazil, who were victims of accidents with biological material in relation to the care and specialized clinical follow-up. Material and method: it is a cross-sectional study which was approved by the Research Ethics Committees of the studied Hospital and of the Ribeirão Preto College of Nursing, University of São Paulo. The study population consisted of 1,215 nursing professionals, who were interviewed in the period from June, 1st 2010 to May, 30rd 2011. Results: of the 1,215 nursing professionals interviewed, 636 (52.3%) have experienced at least one accident with biological material throughout their professional experience, 454 (71.4%) sought specialized care at the Outpatient Clinic for Occupational Accident among Health Care Workers (AOPS) and 26 (5.7%) discontinued the clinical follow-up before the recommended period, and the reasons most frequently reported were delayed care (26.9%), patients with negative serology (23.1%) and forgetfulness (15.4%). 168 injured professionals (37.0%) had an indication for antiretroviral therapy, being that 109 (64.9%) of them had adverse effects and 52 (31.0%) abandoned therapy. Having adverse effects was the most frequently reported reason for discontinuation of antiretrovirals (94.3%). It is highlighted that 182 injured professionals did not seek care at the AOPS and the majority, i.e. 115 (63.2%) professionals, reported not seeking it, because they believed that the accident was at low risk. Conclusion: identifying the reasons why professionals do not seek care and not complete the treatment and the clinical follow-up may contribute to the proposition of strategies to increase professionals\' adherence to the prophylaxis measures after occupational exposure to biological material, and therefore minimize the risk of seroconversion to HIV and HBV, and identify early HCV seroconversion, since there is not, so far, chemoprophylaxis to minimize the risk of seroconversion to this virus.

Aus Punkt 1: "Jährlich werden in Deutschland etwa 15.000 Patienten mit thermischen Verletzungen stationär behandelt, davon etwa 1.400 Fälle mit schweren und schwersten Verbrennungen intensivmedizinisch in spezialisierten Verbrennungszentren. 20-30% der Patienten sind Kinder. Obwohl die Überlebenswahrscheinlichkeit auch von Patienten mit schwersten thermischen Verletzungen (80 %–90 % verbrannte Körperoberfläche, vKOF) in den letzten Jahrzehnten deutlich erhöht werden konnte, liegt die Sterblichkeitsrate noch immer bei ca. 20 %. (Hartmann & Ottomann 2009, Pallua & von Bülow 2006)"

Mycobacterium abscessus est une mycobactérie pathogène émergente à croissance rapidecapable d’induire des infections pulmonaires sévères, notamment chez les patients atteints demucoviscidose. Naturellement résistant à la plupart des antibiotiques disponibles, sa présence peut êtreune contre-indication à la greffe pulmonaire chez ces patients. De plus, l’efficacité des traitementsactuellement préconisés est très fluctuante d’un individu à l’autre et s’accompagne souvent d’effetssecondaires indésirables. Il apparaît donc urgent de développer des stratégies thérapeutiques innovanteset/ou d’identifier de nouvelles cibles pharmacologiques dans la lutte contre ce pathogène. Ce projet dethèse, focalisé sur M. abscessus, est centré sur l’étude mécanistique et fonctionnelle des transporteursmembranaires de la famille des MmpL (Mycobacterial Membrane Protein Large) en rapport avec leur rôledans i) l’élaboration de l’enveloppe mycobactérienne, ii) la physiopathologie infectieuse et iii) leurvalidation en tant que cible d’intérêt thérapeutique.Ainsi, mes travaux ont permis de mettre à jour le rôle clé de MmpL4a dans le transport desglycopeptidolipides (GPL) chez Mycobacterium bolletii, une sous-espèce du complexe M. abscessus et dedémontrer sa participation dans la formation de biofilms, des cordes mycobactériennes et dans la virulencede M. bolletii chez l’embryon de zebrafish. De plus, ces résultats mettent en exergue l’importance derésidus critiques impliqués dans l’établissement de la force proto-motrice, conservés chez toutes les MmpL,et nécessaires à l’activité de ces transporteurs. Enfin, ces études ont abouti à l’identification d’une nouvelleentité chimique très active contre M. abscessus à la fois in vitro et in vivo. Ce composé phare est capable decibler le MmpL3, conduisant à une inhibition du transport des acides mycoliques, connus comme étant descomposants essentiels chez les mycobactéries. Ces travaux représentent le premier exemple d’un inhibiteurciblant spécifiquement le transport d’acides mycoliques chez M. abscessus, ouvrant la voie vers desapplications thérapeutiques prometteuses. / Mycobacterium abscessus is a rapid- growing mycobacterial species and an emerging pathogen,responsible for severe lung infections, particularly in cystic fibrosis patients. Naturally resistant to mostcurrently available antibiotics, its presence can represent a contraindication to subsequent lungtransplantation in these patients. That the currently recommended treatments present fluctuating resultsamong patients and are often associated with important side effects, imposes to develop innovativetherapeutic strategies and/or to identify new pharmacologically relevant targets in the fight against thispathogen. This project, focusing on M. abscessus, is intended to explore mechanistic and functionalaspects of members of the MmpL (Mycobacterial Membrane Protein Large) family of membrane proteinswith respect to i) their role in elaboration of the mycobacterial envelope, ii) their involvement in thephysiopathology of the infection and iii) their validation as potentially attractive therapeutic drug targets.In this context, my studies unraveled the key role of MmpL4a in the transport of glycopeptidolipids (GPL)in Mycobacterium bolletii, a sub-species of the M. abscessus complex and demonstrated its implication inthe formation of biofilms, cording and virulence of M. bolletii in infected zebrafish. Moreover, theseresults put forward the importance of critical residues, conserved in all MmpL members, involved in theestablishment of the proton-motive force required for the activity of these transporters. Finally, thesestudies succeeded in the identification of a new chemical entity exhibiting a potent activity against M.abscessus both in vitro and in vivo. This hit compounds targets MmpL3, leading to the inhibition of thetransport of mycolic acids, known to represent essential components of the mycobacterial cell wall. Theseresults emphasize the mode of action of the first specific inhibitor of mycolic acid transport in M.abscessus, paving the way to promising therapeutic applications.

Aus Punkt 1: "Jährlich werden in Deutschland etwa 15.000 Patienten mit thermischen Verletzungen stationär behandelt, davon etwa 1.400 Fälle mit schweren und schwersten Verbrennungen intensivmedizinisch in spezialisierten Verbrennungszentren. 20-30% der Patienten sind Kinder. Obwohl die Überlebenswahrscheinlichkeit auch von Patienten mit schwersten thermischen Verletzungen (80 %–90 % verbrannte Körperoberfläche, vKOF) in den letzten Jahrzehnten deutlich erhöht werden konnte, liegt die Sterblichkeitsrate noch immer bei ca. 20 %. (Hartmann & Ottomann 2009, Pallua & von Bülow 2006)"