WP6 - Study of CRS pathology and therapy [Months: 3-48]

INSERM

Description and role of ESRs / beneficiaries / partner organizations:

In this WP, we will use a combination of in vitro studies, animal models and patient cohorts to examine:

 

Task 5.1: Novel therapeutic strategies for CRS. ESR5/RDN and ESR6/INSERM will test strategies to reduce CRS pathology in animal models, with a focus on vascular calcification. ESR5/RDN will test the effect of pep-tides CBF and VIF, recently identified by UKA1/MUW to influence vascular calcification and reactivity in vitro, on CRS in vivo. Further, ESR5/RDN and ESR6/INSERM will collaborate to study the role of newly identified CKD biomarkers in CRS pathology in animal models. These CKD biomarkers were recently identified in the EU project iMODE-CKD, and based on literature mining are associated with CV events in non-CKD patients.

 

Task 5.2: Reveal underlying mechanisms of increased vascular calcification and aging in CKD patients to reveal novel therapeutic strategies. ESR7/CARIM will study the effect of uremia on the phenotype and calcification potential of VSMCs and identify uremic toxins from dialysate that increase VSMC calcification in CKD patients. ESR8/UKA2 will focus on vitamin K, a crucial cofactor in the activation of the calcification inhibitor MGP: ESR8/UKA2 will examine whether vitamin K-deficiency is a mediator of vascular calcification in CKD, as UKA2 showed that high dose vitamin K administration reverts levels of uncarboxylated MGP (inactive MGP) in animal models. Of note, UKA2 recently demonstrated again its ability to coordinate multi-centre clinical trials investigating novel therapies in the context of renal disease. ESR9/DSM will identify PTMs of calcification regulators as link between CKD and CVD in CRS. ESR10/ KI will study premature vascular aging and biomarkers of vascular calcification in CKD, based on a finding of partner KI that plasma levels of sclerostin inform on vas-cular calcification in CKD patients. ESR7-10 will be trained to optimize methods to examine calcification and study animal models of CKD, CRS and vascular calcification, as well as plasma, urine and biopsies from patients.

 

Task 5.3: Reveal the direct effect of uremia on VSMCs and cardiomyocytes. ESR7/CARIM and ESR11/UKA1 will examine the effect of uremia on the phenotype/function of VSMCs (ESR7/CARIM) and car-diomyocytes (ESR11/ UKA1) using dialysate from CKD patients, and identify the responsible uremic toxins using chromatography and mass spectrometry in close collaboration with ESR8/UKA2 and ESR1/UKA1.

 

Task 5.4: Proteomics/peptidomics analyses as measure for vascular calcification and CV outcome (and thus CRS) in CKD. ESR1/UKA1 and ESR10/KI will investigate whether plasma can provide quantitative infor-mation on vascular calcification and CV outcome in CKD patients, with a focus on PTMs of calcification regula-tors (ESR9/DSM) or plasma proteins (ESR10/KI) as biomarker candidates for vascular calcification in CKD.