IN CONTROL II

The current IN-CONTROL II proposal is built on the strong fundaments provided by our successful IN-CONTROL I consortium, that unequivocally demonstrated the role and relevance of the microbiome in the development of low-grade inflammation, a hallmark of atherosclerotic cardiovascular diseases, as well as for a number of other risk factors including plasma levels of lipids and microbiome-derived metabolites. These insights are of great relevance to halt the rise in cardiovascular disease-related deaths in our ageing and increasingly overweight population.

The consortium, in this next phase, aims therefore to shift from association to causality, from population-based cohorts to patient groups with atherosclerotic cardiovascular disease (CVD) and from observation to intervention. In this transition, we will also take advantage of recent developments in the network of the consortium, delineating cellular senescence as a druggable target for the broad spectrum of age-related chronic diseases, including cardiovascular diseases, and identification of components of the bile acid-signaling system for this purpose. Another recent development of the recognition of innate immune memory (‘trained immunity’) as pathophysiological mechanism in atherosclerotic CVD.

IN-CONTROL II will seek to i. unravel the mechanisms driving trained immunity in patients, taking into account the impact of senescence, age, sex and obesity, ii. elucidate the interactions between microbiome-derived signals (aromatic amino acids and their metabolites, (secondary) bile acids) and (immune) senescence in the etiology of obesity-related cardio-metabolic diseases, and iii. to identify new therapeutic targets and to design novel pharmacological and microbiome-based therapies to counteract inappropriate induction of trained immunity and inflammatory processes in cardiovascular disease. To do so, we will perform proof-of-principle trials in well-defined patient groups, and make use of state-of-the-art experimental procedures, e.g., systems biology concepts, single cell sequencing, innovative animal models, small animal imaging for cardiac function, next generation –omics and in vivo quantification of metabolic fluxes (fluxomics). A talent program will be put in place to allow all young researchers within the consortium to benefit from the infrastructure provided by the consortium, including its extended network, and to gain insight into all aspects associated with design and development of new treatment modalities for cardiovascular disease. Hence, IN-CONTROL II will have a strong focus on rapid translation of new concepts towards clinical application.

This study is part of a national research consortium sponsored by the Dutch Heart Foundation. Participating centers are: UMC Groningen, Radboud UMC and Amsterdam UMC, in collaboration with Leiden UMC, Wageningen University and Maastricht University.

Talent Program

• The-Marten-Hofker-Talent-Program.pdf