Dr. Heidi Noels and Dr. Yvonne Döring receive the W.H. Hauss Award from the DGAF
19-21 April 2018
Dr. Heidi Noels from the Institute for Molecular Cardiovascular Research at RWTH Aachen University together with Dr. Yvonne Döring from the Institute for Prophylaxis and Epidemiology of Circulatory Diseases at LMU Munich together received the DGAF W.H. Hauss Award 2018 from the German Society for Atherosclerosis Research (DGAF) during the 32nd Annual Meeting of the DGAF in Rauischholzhausen, Germany. They were awarded for their publication "Vascular CXCR4 Limits Atherosclerosis by Maintaining Arterial Integrity: Evidence From Mouse and Human Studies." (Circulation. 2017; 136: 388-403). In this work it could be shown that vascular CXCR4 has an atheroprotective function by maintaining the arterial integrity and preserving the endothelial barrier function. In addition, CXCR4 stabilizes a contractile smooth muscle cell phenotype. Targeted enhancement of these CXCR4-mediated protective functions could open up novel therapeutic options in the treatment of atherosclerosis.
The award was sponsored by a long-standing active member of the DGAF, Prof. Dr. Winfried März.
Project area Z
Administrative project
Robert Werner Mertens
MD student
University Hospital RWTH Aachen
Department of Internal Medicine
Project: The role of incretin hormone GLP-2 in septic cardiomyopathy
PI: Michael Lehrke
Robert Werner Mertens
MD student
University Hospital RWTH Aachen
Department of Internal Medicine
Project: The role of incretin hormone GLP-2 in septic cardiomyopathy
PI: Michael Lehrke
Consortium
Mechanisms of Cardiovascular Complications
in Chronic Kidney Disease
The SFB/TRR219 is supported by the German Research Foundation (DFG)
Project-ID 322900939
Project overview
Alterations in the circulation as well as in the myocardium crucially contribute to the increased cardiovascular risk in patients with CKD. Our consortium SFB/TRR219 will investigate the mechanisms that underlie increased cardiovascular risk in the context of CKD, with a main focus on calcification, inflammation, oxidative stress and fibrosis, in addition to alterations in thrombosis and neurohumoral activity.
Pathological mechanisms underlying increased CVD risk in patients with CKD
-Our joint efforts to examine these mechanisms in the circulation (C projects) as well as in the myocardium (M projects) underlines the interaction between the kidney, circulation and myocardium. Furthermore, the SFB/TRR219 consortium integrates three service projects (S projects) as central platforms. First, a centralized hub for analysing and integrating all clinical studies and experimental data using bioinformatics and statistical methods will facilitate the implementation of experimental concepts into clinical medicine (project S-01). A second platform will provide standardized and harmonized animal models and histopathological analyses of cardiovascular and renal pathology to the consortium to facilitate comparability and synergy between all projects (project S-02). A third project combines chromatography, mass spectrometry and MALDI imaging to enable all consortium partners to gain deep insights into the pathology of CKD-associated cardiovascular disease (project S-03).
-The Central Administration Project (Z project) is responsible for all core functions and for the coordination within the SFB/TRR219 consortium.
-In addition, the SFB/TRR219 consortium has integrated a PhD graduate school (IRTG project) to guide PhD students to become the next generation of innovative, independent and translational cross-disciplinary researchers exploiting multiple facets of cardiovascular disease in CKD.
Complementary approach of our Transregional Collaborative Research Center to investigate in both the circulation and the myocardium the mechanisms underlying increased cardiovascular risk in CKD patients.
Project C-01: Modifying the vitamin K system to halt/regress cardiovascular calcification in CKD patients
Patients with CKD display massively increased cardiovascular calcifications, which contribute to their higher cardiovascular mortality risk. Increased cardiovascular calcification in CKD is triggered, among others, by functional vitamin K deficiency. We identified nutritional compounds that interact with the vitamin K system in vascular calcification processes. We hypothesize that the functional vitamin K deficiency contributes to the uremic toxins load in CKD and that it can be treated to such a degree that we can maximize clinical cardiovascular benefit. Therefore, this project aims to develop a novel nutritional approach in form of a “kidney diet” to reduce cardiovascular calcification in CKD patients.
Project C-02: Sortilin as a target for fibro-calcific remodeling in CKD
The increased cardiovascular risk in CKD patients arises from premature vascular and cardiac aging. We identified the intracellular sorting receptor sortilin as a calcification promotor, with post-translational modification of sortilin in CKD further increasing calcification. Also, our findings suggest a function of sortilin in tissue fibrosis. Therefore, this project will use a translational approach to investigate sortilin as a key target for combating fibro-calcific remodeling in the kidney-cardiovascular axis. We will investigate the underlying mechanism of sortilin-mediated fibrosis and identify sortilin inhibitors for reducing vascular calcification and tissue fibrosis.
Project C-04: Clinical translation of the identified mediators affecting myocardial infarction and vascular calcification in CKD
We contributed towards the elucidation of vascular calcification via the functional characterization of two novel calcification inhibitors, the peptides CBF and VIF. Also, we identified that post-translational modifications (PTMs) in CKD can increase calcification by modifying important calcification regulators. This project will (a) translate CBF and VIF peptide mimetics as therapeutic agents, (b) optimize strategies to scavenge PTMs using free amino acids to improve cardiovascular outcomes in CKD patients, and (c) elucidate the molecular mechanisms of VIF-mediated cardioprotection in cardiac tissue to facilitate targeted drug development for CKD-associated CVD.
Project C-05: Translating high-resolution single cell and spatial omics towards novel therapies for vascular calcification
Vascular calcification strongly contributes to cardiovascular risk in CKD. We could define cell types and pathways involved in vascular calcification and generated advanced single cell and spatial atlases of human vascular calcification to define cell types and molecular mechanisms. We now want to translate this knowledge into the development of therapeutic approaches to prevent and/or reduce vascular calcification. Based on our available omics data, we will identify and prioritize drug targets and perform rigorous drug testing. Also, we will elucidate the molecular basis of calcifying uremic arteriolopathy to identify novel diagnostic and therapeutic targets for prevention and reversal of this disease.
Project C-07: Modulation of the dysregulated alternative complement pathway in CKD
Patients with CKD display alterations in the coagulation system resulting in an increased thrombotic and bleeding risk, which causes an augmented cardiovascular risk in these patients. We recently demonstrated the incorporation of complement C3 into fibrin clots, leading to a prothrombotic clot structure with thinner fibrin fibers and resistance to fibrinolysis. Also the alternative complement pathway plays an important role in complement activation. Based on novel findings, this project aims to modify the dysregulated alternative complement pathway in CKD with the aim to reduce thrombotic risk in these patients.
Project C-08: Role of the extramedullary hematopoietic system as a driver of CKD-associated CVD
CKD represents a pro-inflammatory condition, which drives the development of CKD-associated cardiovascular complications. We identified a reprogramming of the hematopoietic system in the bone marrow of CKD mice and also detected the presence of a hematopoietic system in the kidney, which is altered in response to kidney injury. Therefore, this project aims to unveil important interactions between CKD, CVD and systemic inflammation. We will characterize the contribution of extramedullary hematopoiesis as well as circulating hematopoietic stem and progenitor cells to CVD in CKD and explore the clinical relevance of CKD-associated inflammation in large clinical outcome trials.
Project C-09: Dickkopf-3 (DKK3) and monocytes as therapeutic targets in cardiorenal injury
Tissue fibrosis represents a hallmark of advanced CKD and CVD. Recent experimental work in various CKD models revealed the crucial involvement of the Wnt/β-catenin pathway in the development of tubulointerstitial fibrosis and thus progressive CKD. Dickkopf-3 (DKK3) is a member of the Dickkopf protein family, which is closely involved in the regulation of the Wnt/β-catenin signaling. This project will uncover the role of DKK3 and Wnt/β-catenin signaling as well as deregulated monocytes in tissue fibrosis leading to organ dysfunction in CKD. We will also assess how DKK3 inhibition can be translated into a specific therapeutic target to reduce cardiovascular complications in CKD patients.
Project area C - Circulation
Project area M - Myocardium
Project M-01: PDGF ligand-mediated signaling in increased cardiovascular risk in CKD
We have previously defined the role of PDGFR in CKD, particularly in mediating fibrosis and angiogenesis. Furthermore, we recently revealed that PDGFR activation is involved in both CKD-associated vascular calcification and cardiomyopathy. Therefore, this project now aims to examine the role of PDGF ligands, particularly the most potent ligand PDGF-B, in uremic cardiomyopathy and vascular calcification in CKD. This could serve as a basis for future translation of PDGF-based therapies to prevent or modulate uremic cardiomyopathy and vascular calcification, ultimately improving cardiovascular outcomes in CKD patients.
Project M-02: Effects of neuromodulation on pro-arrhythmic atrial remodeling and ventricular function in CKD-associated heart failure with preserved ejection fraction (HFpEF)
CKD is associated with atrial pro-arrhythmic remodeling and activation of the sympathetic nervous system, a known trigger for atrial fibrillation. We could show that renal denervation inhibits the development of an atrial fibrillation substrate and prevents progression of uremic cardiomyopathy. We now hypothesize that activation of the sympathetic nervous system represents a fundamental pathomechanism contributing to CKD-associated HFpEF. This project will reveal whether renal denervation alone or in combination with SGLT2 inhibition can improve impaired cardiac and renal function in patients suffering from CKD-associated HFpEF.
Project M-03: Modulation of metabolic and functional changes in uremic cardiomyopathy
CKD induces processes of accelerated aging in the heart, termed uremic cardiomyopathy (UC), leading to cellular senescence, degeneration and fibrosis by yet incompletely understood mechanisms. This project will provide further mechanistic insights into altered cardiac metabolism in CKD and will also reveal the role of PYY in CKD and CKD-associated CVD. Translation of these findings into clinical practice could lead to innovative approaches such as PYY receptor modulation to reduce cardiovascular morbidity and mortality in CKD patients.
Project M-04: Calcium and oxidative stress modulation as novel therapy to reduce ferroptosis-induced cardiovascular risk in CKD patients
Inflammation is a major factor determining progression of CKD and the development of cardiovascular complications. This project aims to investigate how calcium and ROS signaling drive ferroptosis and contribute to CKD-associated CVD. By uncovering the molecular pathways regulating ferroptosis, ROS and calcium dynamics under uremic conditions, we aim to identify biomarkers, therapeutic targets and strategies to prevent tissue damage and improve outcomes in CKD-associated CVD.
Project M-05: Translational approaches targeting myocardial and endothelial dysregulation in CKD
Patients with CKD often present with uremic cardiomyopathy and suffer from an increased mortality after myocardial infarction. We found that CKD increases oxidative stress responses in the heart and predisposes the heart to increased cardiac dysfunction post-infarction. This project will now study in more detail the impact of CKD-induced molecular alterations in cardiomyocyte and endothelial function in the context of ischemic, respectively, non-ischemic conditions, and explore novel therapeutic strategies to target dysregulated cellular metabolism in CKD, with a focus on pantothenic acid metabolism.
Project M-07: Immune cell-lipid interaction, a mechanism of CKD-induced accelerated atherosclerosis
Patients with CKD show aggravated atherosclerosis and vascular complications. We observed that CKD triggers the post-translational guanidinylation of Apolipoprotein A-I (ApoA-I, the primary protein of HDL), altering ApoA-I from a protective to pro-inflammatory protein. Also, we provided new insights into intestinal integrin-β7+ intraepithelial lymphocytes (IELs), known drivers of atherosclerosis formation. This project now aims to validate targeting of β7+ IELs as a therapeutic approach against CKD-induced accelerated atherosclerosis formation and elucidate the relevance of post-translationally guanidinylated ApoA-I and macrophage interaction.
Project M-08: Dissection of platelet-macrophage-fibroblast interaction in CKD-driven cardiac remodeling
We recently identified a platelet-macrophage-fibroblast interaction as a major driver of maladaptive cardiac remodeling in heart failure. This project aims to molecularly map CKD-induced cardiac remodeling in mice and patients at an unprecedented resolution to dissect aberrant platelet-macrophage-fibroblast crosstalk in maladaptive cardiac remodeling. The insights gained will guide the identification of novel therapeutic targets and the development of targeted interventions to prevent or reverse cardiac dysfunction in CKD patients.
Project area S – Service projects
Project S-01: Translational integration and evaluation of experimental concepts by evaluation of cohorts from clinical studies, international registries and center-based cohorts
Within the previous funding periods, this service project has intensively supported the entire consortium in the translation of experimental hypotheses into clinical practice through biobank coordination. This service project will now continue to enable and support the clinical translation of experimental research findings in this consortium. By combining insights from consortium-wide research, local validation efforts and global datasets as well as novel AI-based methods, this service project aims to further bridge the gap between discovery and clinical implementation to support the translational goals of the SFB/TRR219 in its 3rd funding period.
Project S-02: Central platform of standardized CKD-CVD animal models and histopathological analyses
This central platform provides intensive support to all researchers of SFB/TRR219 in standardized animal models for CKD-CVD and reproducible tools for the assessment of cardiac and renal histopathology in both animal and human tissues. In this context, this platform has intensively and successfully cooperated with all consortium partners within the previous funding periods. For the third funding period, this service project aims to continue this intensive support and collaboration with the entire consortium by supporting animal modeling of CKD-CVD and histopathological analysis, including computational pathology, of both preclinical and clinical specimens.
Project S-03: Mass spectrometry to identify, quantify and localize novel regulators of pathological processes underlying CKD-associated CVD
This service project transitions seamlessly from identifying novel mediators and understanding post-translational modifications to characterizing the metabolites driving these processes. Mass spectrometry remains central to the SFB/TRR219 consortium, providing unparalleled precision and sensitivity to bridge fundamental discoveries with clinical translation. As a critical hub for proteomics, peptidomics and metabolomics, this project will advance our understanding of CKD-associated CVD, translating insights into actionable clinical strategies to improve patient outcomes.
Project area IRTG – Integrated Research Training Group
Project IRTG: Integrated Research Training Group: Cardiovascular complications in CKD
Within the first funding period of the SFB/TRR219, we established the integrated Research Training Group (IRTG) "Cardiovascular complications in CKD" intending to provide an interdisciplinary training program to all doctoral researchers (PhDs and MDs) associated with the consortium. Our structured curriculum during the second funding period will build on our well-established structures, with the aim to guide our doctoral students to become the next generation of innovative, independent, and translational cross-disciplinary researchers in the interdependencies of the cardiorenal system and beyond to discover innovative solutions in diagnosis and therapy.
Project area Z – Administrative project
Project Z-01: Central administrative project
The Z project is the administrative project of SFB/TRR219. It serves to organize all the joint tasks within the SFB/TRR219. This includes the distribution of the funding, the coordination and administration, the organization of seminars and meetings of the SFB/TRR219 including travel, and all the logistics including internet activities and public relations.