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Targeting perivascular myofibroblast progenitors to treat cardiac fibrosis and heart failure in chronic kidney disease

Objective

Chronic kidney disease (CKD) is a growing public health problem with a massively increased cardiovascular mortality. Patients with advanced CKD mostly die from sudden cardiac death and recurrent heart failure due to premature cardiac aging with hypertrophy, fibrosis, and capillary rarefaction. I have recently identified the long sought key cardiac myofibroblast progenitor population, an emerging breakthrough that carries the potential to develop novel targeted therapeutics. Genetic ablation of these Gli1+ perivascular progenitors ameliorates fibrosis, cardiac hypertrophy and rescues left-ventricular function. I propose that Gli1+ cells are critically involved in all major pathophysiologic changes in cardiac aging and uremic cardiomyopathy including fibrosis, hypertrophy and capillary rarefaction. I will perform state of the art genetic fate tracing, ablation and in vivo CRISPR/Cas9 genome editing experiments to untangle their complex mechanism of activation and communication with endothelial cells and cardiomyocytes promoting fibrosis, capillary rarefaction, cardiac hypertrophy and heart failure. To identify novel druggable targets I will utilize new mouse models that allow comparative transcript and proteasome profiling assays of these critical myofibroblast precusors in homeostasis, aging and premature aging in CKD. Novel assays with immortalized cardiac Gli1+ cells will allow high throughput screens to identify uremia associated factors of cell activation and inhibitory compounds to facilitate the development of novel therapeutics.
This ambitious interdisciplinary project requires the expertise of chemists, physiologists, biomedical researchers and physician scientists to develop novel targeted therapies in cardiac remodeling during aging and CKD. The passion that drives this project results from a simple emerging hypothesis: It is possible to treat heart failure and sudden cardiac death in aging and CKD by targeting perivascular myofibroblast progenitors.
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Host institution

UNIVERSITAETSKLINIKUM AACHEN

Address

Pauwelsstrasse 30
52074 Aachen

Germany

Activity type

Higher or Secondary Education Establishments

EU Contribution

€ 1 497 888

Beneficiaries (1)

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UNIVERSITAETSKLINIKUM AACHEN

Germany

EU Contribution

€ 1 497 888

Project information

Grant agreement ID: 677448

Status

Ongoing project

  • Start date

    1 May 2016

  • End date

    30 April 2021

Funded under:

H2020-EU.1.1.

  • Overall budget:

    € 1 497 888

  • EU contribution

    € 1 497 888

Hosted by:

UNIVERSITAETSKLINIKUM AACHEN

Germany