Gout is one of the oldest rheumatological diseases and affects about 1% of the world’s population.
Uric acid crystal deposition induces inflammation in the joints, which causes extreme pain in gout.
Recent evidence, however, shows that uric acid has major implications in other inflammatory / metabolic pathologies (e.g. metabolic syndrome, atherosclerosis). The mechanism by which uric acid induces the inflammatory cascade and activates the immune system is, to date, unclear.
The hypothesis of our study is that uric acid in high concentrations (independent of crystals precipitation) induces epigenetic and transcriptional reprogramming in the cells of the immune system, resulting in a hyperinflammatory status.
Our project uses complementary techniques of genetics, epigenetics, transcriptomics, metabolomics and immunology to answer these scientific questions.
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Motivation and context of the project
The national and international context in the area of the project
Gout is one of the oldest described rheumatic diseases which affects approximately 1% of the world’s population and reaches 2.5-3.9% prevalence in developed countries. This spectrum of metabolic disorders is the leading cause of morbidity worldwide and has 40-50% mortality rates in the United States and European countries, including Romania.
Uric acid is the metabolic product of purine degradation (substances which are abundant in meat, seafood, and other common foods). Moreover, uric acid is considered an endogenous danger signal released in cellular stress. Recently, our group has discovered that uric acid exerts proinflammatory effects directly on blood cells.
Uric acid is a metabolite formed as a breakdown product of purines (which are abundant in meat, seafood, and other common foods) and moreover, it is regarded as an endogenous danger signal released during cellular stress. Recently, our group has discovered that uric acid also has pro-inflammatory properties, directly affecting blood cells.
Novelty and originality
The novelty of this research is extremely high, on both national and international scale, because the importance of such mechanisms in the common diseases of the adult has very recently emerged.
The research team led by this project’s manager at the Radboud UMC Center in the Netherlands first established that cells exposed to uric acid produced more Interleukin-1β (a protein that induces inflammation in gout and other diseases) and that this is most likely due to an epigenetic phenomenon.
Starting from the results of our study on the long-lasting effects of uric acid exposure, we propose the concept that uric acid constitutes a signal capable of inducing epigenetic reprogramming of non-specific immune system cells, and that this mechanism may be a therapeutic target in autoimmune rheumatologic diseases and metabolic processes. An illustration of this hypothesis is shown in the illustration below.
Metabolic imprinting and the memory of cells of the innate immune system represent new research directions of major interest in the international scientific community.
The development of this project at the “Iuliu Haţieganu” University of Medicine and Pharmacy in Cluj-Napoca helps to characterize Romania’s population in terms of functional genetic analysis in gout and cardiovascular disease and also contributes to the discovery of the mechanisms of imprinting in an international context.
Objectives of the Project
The hypothesis of our study is that uric acid, in high enough concentrations (independent of crystal precipitation), induces epigenetic and transcriptional reprogramming in the cells of the immune system, which determines a high inflammatory status.
The study has 5 major objectives:
- Assessing the capacity of uric acid to induce metabolic imprinting in in innate immune cells
- Validating the epigenetic and molecular pathways identified above in patients with gout and with cardiovascular disorders
- Assessing whether gene variants in key factors associated with these inflammatory and epigenetic processes are linked to the susceptibility
- Assessing whether therapy based on epigenetic modulators can restore immune balance
- Investigating whether therapy in humans can restore the epigenetic state and change the cytokine profile
We envisage that after 4 years we will have elucidated the molecular mechanism of metabolic imprinting by uric acid and we will have identified novel risk factors and therapeutic targets against inflammation.
Total financing value
9,352,330 RON, of which the non-reimbursable financial assistance 8,617,499.04 RON
Period of implementation
“Iuliu Haţieganu” University of Medicine and Pharmacy – Medical Genetics Discipline, Loc. Cluj-Napoca; Louis Pasteur Street, No. 6
Project co-financed from the European Regional Development Fund through the Competitiveness Operational Programme 2014-2020.
Contact: Radu Anghel Popp, e-mail: firstname.lastname@example.org, phone: 0750774406