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Master's Dissertation
DOI
10.11606/D.42.2019.tde-28112018-103757
Document
Author
Full name
Rudá Prestes e Albuquerque
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2018
Supervisor
Committee
Ferreira, Julio Cesar Batista (President)
Cunha, Fernanda Marques da
Diniz, Gabriela Placoná
Tanaka, Leonardo Yuji
Title in Portuguese
Desenvolvimento de novas estratégias para a minimização do dano de isquemia-reperfusão.
Keywords in Portuguese
Autofagia
Carbonilcianeto m-clorofenil-hidrazona (CCCP)
Cardioproteção
Clivagem de OPA-1
H9c2
Isquemia-reperfusão
UPRam
Abstract in Portuguese
O processo de isquemia-reperfusão é responsável pela geração de um dano agudo em uma série de órgãos do corpo humano, e, no coração, é o principal causador da doença crônica conhecida por insuficiências cardíaca. Atualmente não existe nenhuma opção terapêutica disponível na prática clínica contra esta injúria. Com o objetivo de desenvolver uma nova estratégia de combate a este dano, no presente trabalho investigamos a promessa da aplicação da recém-descoberta via UPRam num modelo de hipóxia reoxigenação in-vitro, sem obter sucesso. Contudo, os resultados gerados nestes experimentos forneceram pistas de que o uso do desacoplador CCCP é capaz de reduzir o dano deste insulto, porém o mecanismo celular responsável por esta proteção permanece desconhecido. Tentativas de desvendar este mecanismo utilizando a via lisossomal-autofágica ou a clivagem de OPA-1 falharam, mas produziram importantes insights a respeito do papel da protease mitocondrial OMA-1 no processo de hipóxia-reoxigenação, abrindo caminho para novos estudos subsequentes.
Title in English
Development of novel strategies for mitigating ischemia-reperfusion damage.
Keywords in English
Autophagy
Carbonyl cyanide m-chlorophenyl hydrazine (CCCP)
Cardioprotection
H9c2
Ischemia-reperfusion
Opa-1 cleavage
UPRam
Abstract in English
Ischemia-reperfusion injury is a process that occurs in many human organs including the heart, where it is the main trigger to heart failure, a chronic disease that kills over 40% patients only five years following the first diagnosis. Despite the bulky research on the subject, there is no available therapy on clinical practice against this insult. Attempting to develop a novel strategy to mitigate this damage, we investigated if the pro-survival effect of the recently discovered UPRam pathway could be protective in an in-vitro model of ischemia reperfusion. Despite the negative results regarding its conservation on mammalian cells, treatment with the mitochondrial uncoupler CCCP was proven to reduce cell death under this process, but the cellular mechanism responsible for this protection remained elusive. Aspiring to unravel this cellular response, we tested whether autophagy or OPA-1 cleavage was capable of abrogating the verified protection, but the results came back negative. Regardless of that, the behavior of OMA-/- cells over H/R stress has given new insights on novel strategies comprising I/R injury abrogation.
 
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Release Date
2020-11-27
Publishing Date
2019-01-04
 
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