Out of the box grant call 2017

The talent program has resulted in recruitment of talent and activities not only from within but also from outside the consortium stimulating collaborations with new partners (MUMC and AMC) and strengthening the link with other large research consortia, including CVON-DOSIS, CVON-PHAEDRA and Queen of Hearts.

The following Out of the Box grants have been awarded in 2017:

 1. A. Uitterdijk – “Exosome Nano-intervention for a multi-morbidity translational model of cardiovascular disease and metabolic derangement: A Pragmatic Off-The-Shelf Approach.” (Erasmus MC, Supporting partner Dr. D. Merkus).

“As part of the young talent program, André Uitterdijk was awarded a Proof-of-Concept award titled: “Exosome Nano-intervention for a multi-morbidity translational model of cardiovascular disease and metabolic derangement: A Pragmatic Off-The-Shelf Approach.” Current efforts focus on arranging the local infrastructure including relevant training for generating, isolating, quantifying, sizing and visualization of relevant nano-vesicles. This part is currently 90% complete and generation of vesicles will commence shortly. A potential protective role of these vesicles will first be tested in the ZSF-1 model.”

2. M. Waddingham – “Boosting Endogenous Small Heat Shock Protein Expression to Improve the Myocardial Stretch Response in HFpEF.” (VUMC, Supporting Partner prof.dr. W.J. Paulus)

“The goals of the project, Boosting Endogenous Small Heat Shock Protein Expression to Improve the Myocardial Stretch Response in HFpEF, were to understand if using a small heat shock protein (sHSP) boosting drug, geranylgeranylacetone (GGA) could prevent the development of titin-based cardiomyocyte stiffness and preserve the myocardial stretch response. We treated 20-week old obese ZSF1 hybrid rats with GGA (200mg/kg/day) for 4 weeks. GGA treatment prevented the development diastolic dysfunction and lowered titin-based cardiomyocyte stiffness in Obese ZSF1 rats. Lower titin-based cardiomyocyte stiffness in GGA-treated Obese ZSF1 rats could not be further enhanced with recombinant sHSPs, suggesting that the observed sHSPs boosting effect by GGA may directly lowered titin-based cardiomyocyte stiffness.”

3. L. Medzikovic – “Nuclear receptor Nur77 as potential modifier gene in heart failure.” (AMC, Supporting partner prof.dr.G. Pasterkamp)

 “We aim to correlate patient (HELPFul cohort, n= 299) plasma NPY and Nur77 SNPs as biomarkers for severity of HF. We have analyzed the relationship between plasma NPY and known risk factors of diastolic dysfunction and heart failure and have made a delineation between male and female patients. We still have to analyze the relationship between plasma NPY and other parameters measured in the HELPFul cohort of which we see a phenotype in our Nur77-KO mice. We secondly aim to investigate Nur77 SNPs in human iPSC-cardiomyocytes, however, the expansion of the iPSC cells proved challenging and is a work in progress. Lastly we aim to identify novel Nur77 target genes involved in cardiomyocyte [Ca2+]i homeostasis. We have isolated RNA from the cardiac left ventricles of WT, full-body Nur77-KO and cardiomyocyte-specific-KO mice, which we have phenotypically characterized (n=4/group), to send out for RNA sequencing”

4. M.M. Brandt – “The role of the unfolded protein response (UPR) in hearts of patients with chronic kidney disease.” (ErasmusMC/UMCU, Supporting partners Dr. C. Cheng and Dr. J.Joles)

 “We proposed to evaluate whether renal dysfunction-induced cardiac endoplasmic reticulum stress, resulting from suppressed UPR activation, participates in pathological left ventricle (LV) remodeling. To test this hypothesis, experiments were conducted on cardiac material from normal versus obese ZSF1 rats, which were shown to spontaneously develop diastolic dysfunction preceded by a decline in renal function as a result of the animals’ obesity and diabetes background of risk factors. Study goals involved assessment of UPR dynamics in the LV by means of RNA sequencing and immunohisto-chemistry of cardiac cross sections. Over the last months, lean and obese ZSF1 rats were monitored for diastolic- and renal dysfunction. At the age of 26 weeks, the rats were sacrificed after which the LV was processed for RNA sequencing, and immunohistochemistry. Sequencing results are expected in the first half of May, after which targeted assessment of UPR markers will be carried out in a cell specific manner on the LV cross sections”

5. O. Sequeira – “Energy insufficiency-mediated ADP elevations as cause of diastolic dysfunction.” (VUMC, Supporting partners prof.dr. M.C Verhaar and prof.dr. D.J.G.M Duncker)

“As part of the young talent program, Vasco Sequeira was awarded a Proof-of-Concept award titled: “Energy insufficiency-mediated ADP elevations as cause of diastolic dysfunction“. To that purpose, he initiated studies in humans and animal models of heart failure with diastolic dysfunction, including human hypertrophic cardiomyopathies (HCM), to determine the quality of the energy-buffering systems responsible for maintaining ADP levels low. Vasco found those systems are substantially reduced in HCM samples from both models. This part of the study is currently finished and it will move to the use of pig samples with diastolic heart failure. Validation that the energy buffering systems are diminished also in the pig model will provide support that energy insufficient is central for the progression of diastolic heart failure.”

6. Y. Oligschlaeger – “Plasma cathepsin D activity as a novel tool to connect heart failure, preserved ejection fraction and renal dysfunction.” (MUMC, Supporting partner prof.dr. A.A. Voors).