Report

Teaser, summary, work performed and final results

Periodic Reporting for period 2 - CureCKDHeart (Targeting perivascular myofibroblast progenitors to treat cardiac fibrosis and heart failure in chronic kidney disease)

Teaser

Chronic kidney disease (CKD) is a growing public health problem and affects more than 10% of the population in Europe. CKD patients suffer from a massively increased cardiovascular morbidity and mortality. This is due to vascular calcification and atherosclerosis as well as...

Summary

Chronic kidney disease (CKD) is a growing public health problem and affects more than 10% of the population in Europe. CKD patients suffer from a massively increased cardiovascular morbidity and mortality. This is due to vascular calcification and atherosclerosis as well as cardiac remodeling with fibrosis, hypertrophy and capillary loss. The cellular and molecular mechanisms of vascular and cardiac remodeling in CKD are incompletely understood. We recently identified perivascular progenitors as a major source of cardiac fibrosis and vascular calcification and we propose that signaling from these progenitors is critically involved in all major pathophysiologic changes in cardiac aging and uremic cardiomyopathy including fibrosis, hypertrophy and capillary rarefaction as well as vascular remodeling. We are aiming to dissect the complex interaction between cardiac cell populations including perivascular progenitors to understand cardiac remodeling in CKD with the ultimate goal to identify novel therapeutic targets and develop novel targeted therapeutics for the vast and growing patient population suffering from cardiac remodeling in CKD.

Work performed

We have established several novel high-throughput single cell genomic technologies to dissect cellular and molecular mechanisms of cardiac remodeling in CKD and aging. Furthermore, we have performed genetic fate tracing experiments in cardiac remodeling in CKD and non-CKD to understand the cell-populations that contribute to cardiac remodeling. We have started to combine genetic fate tracing with single cell genomics to understand cell-heterogeneity and cross-talk in homeostasis and disease. We have further generated novel reporter cell-lines of cardiac myofibroblasts (scar forming cells that drive disease) to perform various screenings with the ultimate goal to identify novel therapeutic targets (e.g. whole genome CRISPR screening and also for high-throughput measurement of proliferation in regard to uremic toxins in CKD). The first screenings are currently being performed.

Final results

We are expecting to identify and validate several novel therapeutic targets for heart failure and heart failure with CKD. Furtehrmore we might also identify prognostic measures for uremic cardiomyopathy.