Projectdetails

of


Systemic oxidative stress in health and disease

Keywords:
oxidative stress Inflammatory bowel disease biomarkers

Researchers:
prof. dr. G. Dijkstra
Prof. dr. H. van Goor
drs. A.R. Bourgonje

Nature of the research:
The student will have the opportunity to participate in an active research line focused on the role of systemic oxidative stress in a variety of diseases.

Fields of study:
gastroenterology internal medicine molecular biology

Background / introduction
Oxidative stress is characterized by increased production of reactive oxygen species (ROS) and decreased antioxidant defense and plays a pivotal role in a variety of human diseases. (1) Generally, oxidative stress is considered as a major disease mechanism responsible for extensive cellular and molecular damage, perpetuation of inflammatory reactions and tissue destruction.
An example of such a disease affected by oxidative stress is inflammatory bowel disease (IBD). (2) IBD is an umbrella term used to describe two main entities: Crohn’s disease (CD) and ulcerative colitis (UC). IBD has a multifactorial disease origin, with a complex interplay between genetics, gut microbiota, the host immune system and lifestyle factors. Patients with IBD typically show a relapse-remitting disease course that is difficult to predict and adequately treat. Nowadays, an invasive endoscopic procedure is the gold standard diagnostic modality to determine IBD disease activity, however, this investigation is accompanied by poor patient acceptance, risk of complications and high costs. For this reason, a large area of research is focused on the discovery of novel biomarkers for inflammatory disease activity in IBD.

Recently, we have investigated serum free thiols (R-SH, sulfhydryl groups) as biomarker for IBD disease activity and found favorable associations with several disease activity markers. (3-4) Free thiols are considered a robust and reliable read-out of systemic levels of oxidative stress. Typically, systemic oxidative stress is associated with decreased free thiol levels, whereas high levels of free thiols are representative of a favorable redox status. (1) In addition, there have been other studies that focused on free thiols as potential biomarker, though in different diseases. For instance, a study in renal transplant recipients investigated serum free thiols and found free thiol levels to be associated with improved patient and graft survival. (5) Another study demonstrated favorable associations of serum free thiols with markers of severity and prognosis of heart failure. (6)

Overall, these results indicate that a simple measurement of total serum thiol status may be highly useful for measuring systemic oxidative stress and may act as potentially predictive tool in future translational research. Since serum free thiols can also be therapeutically modulated, they form a potential target for therapy, which makes them even more interesting and valuable to study.
Research question / problem definition
In this research, we have several questions that we would like to answer:

What is the role of serum free thiols in diseases affected by oxidative stress?

What is the value of serum free thiols as biomarker for disease activity in IBD and related disorders?

What are the effects of therapeutic interventions on systemic oxidative stress?

What is the predictive capacity of serum free thiols regarding response to therapy and disease prognosis?
Workplan
The student will help to discover the possible roles of free thiol status in IBD and other diseases affected by oxidative stress. A large amount of data has already been collected that has to be explored to be able to assess free thiol status as potentially predictive tool for disease-specific outcomes and prognosis. These studies will be clinically-oriented and of translational origin, and an easy shift could be made towards more fundamental research (if preferred). The student will learn a lot about disease mechanisms and develop skills for data analysis and data interpretation.
References
(1) Cortese-Krott MM, Koning A, Kuhnle GGC, Nagy P, Bianco CL, Pasch A, et al. The Reactive Species Interactome: Evolutionary Emergence, Biological Significance, and Opportunities for Redox Metabolomics and Personalized Medicine. Antiox Redox Signal 2017.

(2) Pereira C, Grácio D, Teixeira JP, Magro F. Oxidative Stress and DNA Damage: Implications in Inflammatory Bowel Disease. Inflamm Bowel Dis 2015.

(3) Bourgonje AR, von Martels JZH, Bulthuis MLC, van Londen M, Faber KN, Dijkstra G, van Goor H. Crohn’s Disease in Clinical Remission Is Marked by Systemic Oxidative Stress. Front Physiol 2019.

(4) Bourgonje AR, Gabriëls RY, de Borst MH, Bulthuis MLC, Faber KN, van Goor H, Dijkstra G. Serum Free Thiols Reflect Endoscopic Disease Activity Superiorly to Fecal Calprotectin Levels in Inflammatory Bowel Disease. Manuscript in preparation.

(5) Frenay AS, de Borst MH, Bachtler M, Tschopp N, Keyzer CA, van den Berg E, Bakker SJL, Feelisch M, Pasch A, van Goor H. Serum free sulfhydryl status is associated with patient and graft survival in renal transplant recipients. Free Radic Biol Med 2016.

(6) Koning AM, Meijers WC, Pasch A, Leuvenink HGD, Frenay AS, Dekker MM, Feelisch M, de Boer RA, van Goor H. Serum free thiols in chronic heart failure. Pharmacol Res 2016.
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Laatst gewijzigd: 23 februari 2012