Description

It has recently been recognized that the metabolic state of an organism is decisive in chronic inflammatory diseases such as atherosclerosis. Metabolism in an individual cell may dictate signaling pathways that modulate inflammatory responses and vice versa. This novel conceptual thought is important to consider in future therapeutic metabolic and anti-inflammatory strategies, but more data are necessary to further substantiate this hypothesis before we can start thinking about modulation. Nuclear Receptors are ideal candidates to explore in this respect, since these proteins are at the crossroads linking metabolism to inflammation and small-molecule compounds can regulate their activity.
The research of Carlie de Vries aims to dissect the molecular processes underlying the function of the nuclear receptor Nur77, which is known to modulate metabolism and for which she has demonstrated that it inhibits atherosclerosis. The research program has a strong focus on macrophages, cardiomyocytes, smooth muscle cells and endothelial cells. ChIPseq/RNAseq studies in macrophages have been performed to delineate the downstream signaling of Nur77. Nur77 indeed modulates the expression of genes involved in metabolic pathways and inflammatory processes. So far, no ligands have been identified binding the traditional pocket in the ligand-binding domain, however in silico searches for small-molecule interactions revealed potential alternative binding sites for specific drugs. Dedicated mouse models are operational and allow verification of in vitro observations towards translation in clinical practice.
The activity of Nur77 is regulated by interacting proteins that were identified, such as the peptidyl-prolyl isomerase Pin1 and the LIM-domain only protein FHL2. Follow up studies on FHL2 revealed that this protein is functionally involved in inhibition of smooth muscle proliferation and that FHL2 deficiency attenuates airway inflammation in mice. Moreover, genetic variation in the FHL2 gene associates with human bronchial hyper-responsiveness.



Theme: Cardiovascular Diseases
StatusActive
Effective start/end date1/02/07 → …

ID: 170326