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Project

Identificatie van kleine moleculaire ErbB4 agonisten ter behandeling van cardiovasculaire ziekten.

Neuregulin-1 (NRG-1) is the natural paracrine agonist of the ErbB4 receptor. There is overwhelming evidence that the cardiac NRG-1/ErbB4 system is activated in chronic heart failure (CHF), exerting disease mitigating and regenerative effects. Based on these data from both animals and humans, NRG-1 is developed as a drug for CHF. Clinical trials are performed, and have progressed to stage III (NCT01251406, NCT1214096, and NCT01541202). In addition, there is solid evidence from animals studies that the NRG-1/ErbB4 pathway is involved in other chronic diseases, such as diabetic nephropathy, pulmonary hypertension, atherosclerosis and fibrotic disorders. All of these are common chronic disorders, and potential therapeutic targets for NRG-1. To date, the only way to activate the NRG-1/ErbB4 pathway in vivo is to inject recombinant NRG-1 (rhNRG-1) intravenously. In clinical trials, this is performed over the course of 6-8 hours, which limits applicability of rhNRG-1 in chronic disorders. A small molecule, acting as an ErbB4 agonist would circumvent the drawbacks of a recombinant protein and might be more efficacious in treatment of chronic diseases. Currently, there are no small molecule agonists of ErbB4 identified. In this project, we propose a multi-disciplinary project, including a high throughput experiment using a chemical library to identify agonists of the ErbB4 receptor (OBJECTIVE 1), to test the compound with the highest potency and receptor specificity in validated rodent models of CHF (OBJECTIVE 2), and to define specific patient populations in the heterogeneous field of cardiovascular diseases that could benefit from ErbB4 agonists by quantifying serum levels of neuregulin-1 in human patients (OBJECTIVE 3).
Date:1 Sep 2018 →  31 Aug 2022
Keywords:CARDIOLOGY
Disciplines:Cardiac and vascular medicine, Laboratory medicine, Palliative care and end-of-life care, Regenerative medicine, Other basic sciences, Other clinical sciences, Other health sciences, Nursing, Other paramedical sciences, Other translational sciences, Other medical and health sciences
Project type:Collaboration project