Inhibiting the DNA-repair enzyme 8-Oxoguanine Glycosylase (OGG1) as a novel treatment for acute inflammation – exploring the cellular mechanism of the new inhibitors.
Background: Acute inflammation and associated complications account for a large part of mortality and morbidity in the world. Although great progress has been made in the medical field of inflammation over the past decades, systemic inflammatory response syndrome (SIRS) caused by an infection (sepsis) is still one of the most common causes of death at hospitals. The mortality of severe sepsis is as high as 20-30%, and the cytokine storm causes complications like acute respiratory distress syndrome (ARDS) and multi organ failure. Today there is no effective molecular targeted therapy against sepsis, although numerous clinical studies with different anti-inflammatory compounds have been made. Since the only effective evidence-based treatment today is antimicrobial treatment and usual intensive care, there is an urgent need for new targeted therapies to tackle the high mortality rates. Aim: Our group has many years of experience in targeting DNA-repair enzymes for therapeutic purposes, and in this project, we want to develop a novel type of anti-inflammatory drug. Our chemists have synthetized the OGG1 inhibitor TH5487, which has been found to efficiently suppress inflammation both in vitro and in vivo. We therefore want to explore the anti-inflammatory mechanisms of this compound further, in order to map exactly which parts of the immune system that are affected by the compound. Methods: For this project different cellular methods will be used, like flow cytometry, Western Blot, RT-qPCR and different redox assays to mention a few. The student will culture both cell lines and primary peripheral blood mononuclear cells obtained from fresh buffy coats from the Karolinska Hospital and perform functional immunological tests and explore protein expression. This project offers an opportunity to practice different cellular methods with focus on immunology, and to work with a large team consisting of scientists with backgrounds from both academia and industry. The mixed professions range from basic molecular biologists and biochemists, to pharmacologists and practicing clinicians. Daily supervision will be given by both senior researchers and the PhD-student working on the project. Latest publication on TH5487 and its anti-inflammatory potential: Science 2018 Small-molecule inhibitor of OGG1 suppresses proinflammatory gene expression and inflammation. PMID: 30442810 |
