UMFCLUJ

Hyperuricemia induced inflammation: Prediction of long-term inflammatory complications and targeting of the persistent effects of urate exposure

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Contract no: 760065/23.05.2023

Code: 85/15.11.2022

Project title: Hyperuricemia induced inflammation: Prediction of long-term inflammatory complications and targeting of the persistent effects of urate exposure

Total budget: 7.656.837,98 RON (PNNR 7.000.000 RON plus 656.837,98 RON VAT).

Duration of project: 36 months (between 01.07.2023-30.06.2026)

Project Director: Prof. Dr. LEONARDUS A. B. JOOSTEN, Radboud UMC Nijmegen, Netherlands

The implementation place : Catedra de Genetică al Universitatatii de Medicină și Farmacie “Iuliu Hațieganu” Cluj-Napoca

Summary

The current project aims to investigate patients with gout, asymptomatic hyperuricemia, and controls. During the 36 months of this project, an innovative approach will be developed by analysing new processes such as clonal haematopoiesis with undetermined potential, DNA methylation and age acceleration, the role of immune gene priming long non-coding RNA (immune gene priming long non-coding RNA) in the stability of epigenetic effects and the interaction of metabolic factors in the prediction of the inflammatory response. This will be realised through several scientific aims, including integrated multi-omics studies and comprehensive analysis which will allow the development of new prediction tools to identify people at risk of distant inflammatory events (gout attacks, cardiovascular events). DNA methylation data will be used to assess accelerated aging in correlation with urate levels and urate induced inflammatory priming. This kind of strategy will help to identify feature combinations that can stratify patients into clusters (e.q. fast and slow progression from hyperuricemia to gout, CVD complications, accelerated aging). Also, a comprehensive systems biology approach to integrate large-scale genomic, transcriptomic and cytokine production data will be used to describe the baseline heterogeneity of immunological parameters, to identify inter-correlated immune components, infer functional connections within the immune system and build predictive models of cytokine-production capacity and trained immunity features in response to urate. Therefore, the project will progress from identified associations and mechanisms to functional validations and translation of results to clinical practice.

General aim

To validate initial findings from the HINT I project, implementing a stratification approach for individuals at risk for inflammatory events and to predict individuals that may benefit from personalized prevention in their inflammatory disease long-term follow-up along with the implementation of newly emerged concepts, e.g., IPLs or CHIP.

Specific Objectives

SO1. To expand the knowledge on innate immune reprogramming mechanisms and epigenetic regulation to characterize urate driven inflammation (CHIP mutations, IPLs, metabolomics, DNA methylation)

SO2. To address sources of host variability in urate- inflammation and create framework for personalized care based on biomarker and target discovery

SO3. To assess persistence of trained immunity features, test predictive biomarker combinations and develop therapy targets in hyperuricemia-related diseases (gout, CVD)

Project team HINT-II

• Prof. Dr. Leornadus A.B. JOOSTEN – Project manager
• Prof. Dr. Simona REDNIC - Experienced researcher
• Conf. Dr. Radu POPP - Experienced researcher
• Asist. Univ. Dr. Cristina PAMFIL – Postdoctoral researcher
• Asist. Univ. Dr. Tania CRIȘAN - Postdoctoral researcher
• Dr. Medeea BADII - Postdoctoral researcher
• Drd. Orsolya GAAL – PhD student researcher
• Dr. Georgiana CABĂU – Assistant researcher
• Drd. Valentin NICA – PhD student researcher
• Drd. Ancuța STRATON - PhD student researcher
• Drd. Maria MUNTIU- PhD student researcher
• Drd. Ioana Rebeca TOMA - PhD student researcher