Advanced search
Start date
Betweenand

DNA repair, oxidative stress and metabolic dysfunction in sepsis - investigation of possible therapeutic target

Grant number: 18/18418-5
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): December 01, 2018
Effective date (End): November 30, 2021
Field of knowledge:Health Sciences - Medicine - Medical Clinics
Principal Investigator:Reinaldo Salomão
Grantee:Sidneia Sousa Santos
Home Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
Associated research grant:17/21052-0 - Sepsis: mechanisms, therapeutic targets and epidemiology, AP.TEM

Abstract

Poly(ADP-polymerase)1 (PARP1, the major isoform of a family of poly(ADP-ribosyl)ating enzymes), a constitutive nuclear and mitochondrial enzyme, is a key regulator of DNA repair, cell death and gene expression. In addition to regulating nuclear DNA repair and maintaining genomic integrity, PARP1 functions include: a) regulation of DNA repair, b) regulation of gene transcription, and c) catalytic functions, such as target protein PAR and a downstream. In addition, PARP1 acts as co-activator and co-repressor of gene transcription, thus regulating the production of inflammatory mediators. (Kraus, 2008; Ji & Tulin, 2010; De Vos et al, 2012; Lapucci et al, 2011). In the last two decades, Szabo and colleagues, in addition to other independent researchers, have pointed to the importance of PARP1 in the pathogenesis of various forms of critical illness (Jagtap & Szabo, 2005; Modis et al, 2012). Several studies have shown that PARP1 becomes activated (and "PARilated" proteins increase) in various human pathophysiological conditions, ranging from stroke and myocardial infarction to neurotrauma and diabetic complications (reviewed in Curtin & Szabo, 2013). Among PARP1 antagonists, olaparib has recently been released for the treatment of ovarian cancer by the US Food and Drug Administration (FDA) and the European Regulatory Agency. In Brazil, it was approved by the National Agency of Sanitary Surveillance (Anvisa) for the treatment of maintenance of adult patients with specific carcinomas. Although olaparib was originally developed and optimized for cancer therapy (Huehls et al, 2011; Yamauchi et al, 2014), more recently, preclinical data in several models of organic injury have shown that treatment of olaparib rodents improves renal and pulmonary function in models of endotoxemia and pulmonary inflammation (Kapoor et al, 2015; Ghonim et al, 2015a; Ghonim et al., 2015b). Preliminary data generated by C. Zsabo in a model of endotoxemia in mice show that olaparib improves survival and reduces several markers of organic injury; in the same way, cytoprotective effect of olaparib was evidenced in cells exposed to oxidative stress.Taken together, the data presented here support the hypothesis that the activation of PARP in critical illness is not only a phenomenon observed in animal models of disease, but is part of the pathophysiology of human disease. Thus, the availability of olaparib as the first suitable PARP inhibitor for use in patients opens the way for the expansion of clinical use of PARP inhibitors for non-cancer indications. Sepsis represents a major indication for such use extension efforts because a robust set of preclinical data shows the therapeutic efficacy of various PARP inhibitors.