INTERACTION BETWEEN RESEARCH THEMES AND PARTNERS

 

research

 


Research is structured in the following 4 Themes
:

1. Validation of preclinical disease models and new insights into disease mechanisms.
Several unique rodent models (partner 1,2,4) and a Pkd2 zebrafish model are available (P3-USFD). These models will be used to gain further insight into disease pathogenesis, drug-screening and/or pre-clinical drug testing. Previous studies already indicated time-dependent drug efficacies and complexity of signalling as well as age-dependent dependent propensity to develop cysts, that is related to the peculiar epigenetic bookmarking effect of HNF1 ß on its PKD target genes. In addition, human cystic epithelial cells show significant alterations in miRNA expression compared to normal cells (P3-USFD). An in-depth analysis of genetic and epigenetic alterations will be studied in combination with analysis of signal transduction pathways (P1-LUMC, P6-SXS). Bioinformatic & Biosemantic analysis will be applied to analyze, integrate and interpret these data together with published information (e.g. gene/protein expression profiling, protein-protein interaction, protein atlas, metabolite/pathway databases) in a cross-species meta-analysis approach. The effects of Pkd1-haploinsufficiency will be substantiated in vivo and in vitro on vasopressin
signalling and osmoregulation in mice. This will be compared to osmoregulation in patients with ADPKD at an early stage of disease progression (eGFR > 60 ml/min) (P2-UZH).
ADPKD is a disease characterized by a prominent extra-renal vascular phenotype which includes aneurysm formation and rupture, hypertension and increased angiogenesis in diseased tissue. We
will examine the angiogenic phenotype in Pkd2 mutant zebrafish model to delineate what angiogenic factors mediate the increased angiogenesis observed in this model (P3-USFD).

 

2. Drug screening and testing.
The zebrafish will be used in high-throughput drug screening. We will utilize FDA-approved libraries to assess the effect on both renal and vascular phenotypes in this model (partner 3). Identified lead compounds will be to further validated in unique human cystic cell lines (P3-USFD) and tested in rodent models (P1-LUMC).

 

3. Biomarkers and imaging to develop progression markers and define novel end-points for clinical trials.
Identify and validate tools for (early) prediction of cystic renal disease progression using two main complementary approaches i.e.
(1) Biomarker discovery and validation in the plasma and urine of patients and rodent models using exploratory as well as targeted analysis (P1-LUMC, P2-UZH, P3-USFD, P7-Mosaiques) (proteomics, metabolomics, exosomes).
(2) Improved imaging analysis protocols for CT-scan and MRI analyses will be developed (P4-INSERM, AP3-Orobix).

 

4. Registry/biobanking and getting insights from ADPKD clinical trials.
registries will be harmonized and patient cohorts will be expanded in preparation for future biomarker studies and clinical trials (in collaboration with EuroCYST). Furthermore, efficacy and
safety of drugs in ongoing clinical trials will be monitored. Partner 5 provided the first evidence of the safety and short-term efficacy of octreotide in slowing the time-dependent increase in total
kidney volume and total liver volume, in ADPKD patients. As follow-up, a randomized trial in a larger series of ADPKD patients is ongoing as well as a study for the mTor-inhibitor Sirolimus,
which be evaluated soon. This clinical work will be complemented by the expertise in imaging analysis and studies on urinary biomarkers in collaboration with P2-UZH,  P3-USFD, P7-Mosaiques.