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Doctoral Thesis
DOI
10.11606/T.42.2011.tde-09022012-125807
Document
Author
Full name
José Antonio Tavares de Albuquerque
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2011
Supervisor
Committee
Isaac, Lourdes (President)
Haddad, Luciana Amaral
Starobinas, Nancy
Tambourgi, Denise Vilarinho
Vasconcelos, Dewton de Moraes
Title in Portuguese
Papel da Arg127 na conformação estrutural e secreção de Fator H, importante proteína reguladora da via alternativa do sistema complemento
Keywords in Portuguese
Imunogenética
Imunologia celular
Imunologia médica
Abstract in Portuguese
A Via Alternativa é a principal via de ativação do sistema complemento (SC), sendo o Fator H (FH) um de seus principais reguladores. No presente estudo, nós investigamos os mecanismos moleculares pelo qual o paciente com a mutação Arg127His no FH possui deficiência do SC. Para isto, utilizamos fibroblastos de paciente e individuo normal estimulados com IFN-g e verificamos que as células do paciente eram capazes de produzir FH, contudo a maior parte das proteínas estava retida no retículo endoplasmático (RE). Em paralelo, transfectamos células Cos-7 com plasmídeos contendo a mutação CG453T® CA453T e observamos que a mutação foi responsável pelo retardo na secreção de FH. Apesar da mutação reduzir a secreção de FH, observamos que a capacidade de FH atuar como co-factor não foi afetada. Assim, avaliamos se o uso de chaperonas químicas poderia induzir a secreção da proteína e observamos que houve aumento na secreção de FH nos fibroblastos. Desta forma, propomos o uso desses fármacos como alternativa de tratamento para melhorar a sobrevida do paciente.
Title in English
Role of Arg127 for complement regulatory Factor H structural conformation and secretion.
Keywords in English
Cell immunology
Immunogenetics
Medical immunology
Abstract in English
Factor H (FH) is one of the most important regulatory proteins of the alternative pathway of the complement system (CS). In this study, we investigated the consequences of FH Arg127His mutation to the secretion ratio of this protein by skin fibroblasts in vitro. We stimulated the FH synthesis from patient and normal control with IFNg when we observed that the patient cells were able to synthetize FH, however this mutant protein was mainly retained at the endoplasmic reticulum. In parallel, we transfected Cos-7 cells with plasmids containing CG453T® CA453T mutation and observed that the mutation was responsible for the delay in the FH secretion. Although the mutation reduced the FH secretion, we observed that the FH function was not affected. Thus, we evaluated whether the treatment with chemical chaperones could release FH to the culture supernant. We observed that patients fibroblasts treated increased the secretion of FH. In conclusion, we suggest the use of these chemical chaperones as a potential alternative therapeutic to improve the patients survival.
 
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Publishing Date
2012-03-15
 
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