About myself

Dr Marten Hoeksema is an assistant professor at the Medical Biochemistry department of Amsterdam UMC (University of Amsterdam). He obtained his PhD at the UvA in 2016, studying the epigenetic regulation of macrophages in atherosclerosis. After this, he performed his post-doctoral training (2016-2021) in the lab of prof.dr. Glass at UC San Diego, CA, USA, in which he studied genetic variation and enhancer function in macrophages. Supported by a Marie Curie fellowship, he returned to Amsterdam UMC in 2021, where he now is setting up his own research group. His research, funded by an ERC Starting Grant and a Dutch Heart Foundation Sr. Scientist Dekker fellowship, focusses on identifying the transcriptional regulators that shape the macrophage phenotype in disease states. For this Bertus Kemp stipendium, dr. Hoeksema will collobarate with and visit the lab of dr. Emiel van der Vorst, group leader at the University of Aachen, who is renowned for his work on kinase arrays to identify active signalling pathways in cells.

About the research

Dysregulated macrophage function is a key underlying factor in the development of many inflammatory diseases. Cytokines, small secreted signalling molecules with immunomodulatory functions, influence the phenotype of macrophages and thereby disease states. Although cytokines have very diverse functions, many signalling pathways are similar. After binding to their cytokine receptor, Janus kinase (JAK) proteins and signal transducer and activator of transcription (STAT) transcription factors (TFs) are activated. STATs then shuttle to the nucleus and bind specific recognition motifs in gene enhancers and promoters, thereby regulating inflammatory gene expression.

This leads to an intriguing paradox: how do cytokines with different roles (from pro- to anti-inflammatory) elicit their specific responses despite using similar pathways to activate STATs? This paradox of cytokine specificity is a major challenge in immunological research. It remains unclear how immune cells relay cytokine-specific signals to elicit the appropriate response.

This has implications for the development of anti-inflammatory drugs. JAK inhibitors have shown great promise in the treatment of inflammatory diseases such as rheumatoid arthritis (RA). However, due to their ability to target multiple cytokine pathways, they are also associated with a number of adverse effects. As a result, current research efforts are focused on developing more selective JAK inhibitors. However, these will still affect a variety of cytokine pathways.

Our goal is to identify the specific kinases that are activated in response to cytokine stimulation and to distinguish between cytokine-mediated responses. This knowledge will facilitate the development of more targeted interventions for inflammatory diseases.