There is a considerable shortage of deceased donor kidneys. Hence, more organs of marginal quality need to be considered for transplantation. Transplant centers are increasingly utilizing ex vivo normothermic machine perfusion to better preserve donor kidneys prior to transplantation. Little is known about molecular pathways that are active while the organ is perfused ex vivo. Also, there is hardly any data on which molecular processes are relevant to assess organ quality during perfusion. I aim to determine the molecular mechanisms of ex vivo kidney perfusion prior to renal transplantation in order to develop breakthrough pre-transplant perfusion-based diagnostic markers that can indicate kidney transplant outcomes. First, a series of normothermic ex vivo porcine kidney perfusions will be conducted with repeated tissue and perfusate sampling. Ex vivo measurements will be contrasted with the contralateral kidney that remains in vivo. Genomics, transcriptomics, proteomics and metabolomics, as well as ex and in vivo magnetic resonance imaging followed by radiomics will be employed. Distinct molecular pathways will be identified which characterize an ex vivo perfused kidney, compared to the organ’s behaviour in vivo. Second, the discovered molecular pathways will be validated for human donor kidneys by performing ex vivo perfusions of discarded human organs followed by the same multi-omics approach. Finally, a prospective clinical study will be conducted with human kidneys that are perfused ex vivo prior to transplantation. With artificial intelligence analysis, tissue and perfusate multi-omics measurements and standard clinical variables will be associated with transplant results, to create advanced prediction models for post-transplant outcome. The high gain of my project will be a better understanding of molecular mechanisms during ex vivo kidney perfusion and advanced, personalized pre-transplant prediction models for post-transplant outcome.
The Microbes in Health and Disease research programme at the University Medical Center Groningen (UMCG) proposes the Doctoral Training Programme PRONKJEWAIL (‘a real gem’) in the field of hospital care and infection. The specific training objective is ‘protecting patients with enhanced susceptibility to infections’. PRONKJEWAIL will recruit 16 international ESRs, who will be trained in research, transferable skills, and network and capacity building. They will be guided by experienced supervisors from the departments of Medical Microbiology, Internal Medicine, Intensive Care, Clinical Pharmacy and Pharmacology, Rheumatology and Immunology, Surgery, Cell Biology, and Pharmacoepidemiology and Pharmacoeconomics at the UMCG. 26 partner organisations, including 14 private sector partners, are committed to support ESR training via mentoring, courses and secondments. Research training builds on four Pillars: 1) vaccines and primary prevention; 2) personalized detection and infection prevention; 3) iatrogenic influence on the microbiome and 4) personalized therapy/stewardship. Each Pillar integrates fundamental, translational and clinical/epidemiological training projects. The high exposure to fundamental, translational and clinical research in academia and industry will increase the ESRs future problem-solving capabilities. Further, ESRs will learn to value mobility through internships at international partner organizations. By providing an excellent scientific working environment PRONKJEWAIL will directly impact on hospital care and, ultimately, it will contribute to enhanced public health. By providing excellent training, PRONKJEWAIL will develop new talent within the next generation of medical researchers thereby strengthening the European Research Area.
Understanding how genes and genetic variants influence heart function is of major importance, not only from a basic science viewpoint, but also as a foundation for future innovation in medicine and health-care. In this proposal, Dr. Niek Verweij aims to identify novel genes and mechanisms underlying heart growth. This will be done in collaboration with the top-scientist Dr. Chris Newton-Cheh (Harvard/Massachusetts General Hospital, Broad Institute of Harvard and MIT) and Dr. Laurie Boyer (MIT). As heart growth accompanies many forms of heart disease, this project will focus on the QRS-complex (of the electrocardiogram) in population based studies as this reflects electrically active cardiac mass. We will search for novel low-frequency genetic variants associated with the QRS-complex within the CHARGE consortium and within a Dutch population using dedicated reference panels. Loci will be interrogated through the use of published and unpublished in silico big-data sets to further prioritize variants and regions for experimental follow-up aimed at elucidating biological mechanisms. This project will bridge the gap between population based genetic association studies (with Dr. Newton-Cheh) to functional biology (with Dr. Laurie Boyer). This proposal will provide novel insights into cardiomyocyte functioning and provide novel avenues to study heart disease vulnerability and design innovative treatment.
The overarching objective of STOP-HF is to generate human induced pluripotent stem cells (hiPSC) derived cardiomyocytes from two specific forms of heart failure (HF) with a clear trigger to unravel common pathophysiological mechanisms involved in the early development of HF. The project is focused on two specific forms of HF, both with a clear trigger: pregnancy and anthracyclines. Better understanding of early molecular pathways leading to HF and knowledge about inter-individual susceptibility is needed. For detection of early changes on a molecular level cardiac tissue is needed. Generation of patient specific cardiac cells from skin fibroblasts (hiPSC technology) is a novel and innovative approach. SPECIFIC OBJECTIVES 1. Fabrication and maturation of 3D cardiac tissue from hiPS derived cardiomyocytes. 2. Generate and characterize hiPS derived cardiomyocytes and endothelial cells from females with pregnancy induced HF and unravel differences on transcriptome level. 3. Generate and characterize hiPSC derived cardiomyocytes from patients with high susceptibility and resilience to develop anthracycline-induced HF and compare them on transcriptome level. 4. Integrate the results for coding and non-coding RNAs from objective 1+2 and identify overlapping pathways. 5. Validate discoveries on transcriptome level in vitro, in vivo and apply for the development of HF in the general population. WORKPACKAGES WP1: Optimize fabrication and maturation of 3D cardiac tissue from hiPS derived cardiomyocytes WP 2A:Validate the model and compare hiPS derived cardiomyocytes and endothelial cells from PPCM and healthy sisters on transcriptome level; WP 2B:Validate the model and compare hiPS derived cardiomyocytes from both patients with high susceptibility and resilience to develop HF after anthracyclins on transcriptome level; WP 3:Integration of transcriptome data from WP 2A+2B; WP 4:Validation of novel pathways in vitro, in vivo and new onset HF in the general population.