Project Details
Projekt
Molecular imaging of tissue remodeling in CKD
Subject Area
Nephrology
Term
since 2021
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 445703531
The lack of specific and non-invasive biomarkers for the diagnosis, staging and treatment monitoring of chronic kidney disease (CKD) has hampered the translation of novel drugs from preclinical settings into clinical practice. The extent of renal interstitial fibrosis is currently the best predictor of progression and transition from potentially reversible to irreversible CKD. Histopathological analysis of kidney biopsies is the only available means to specifically assess the extent of renal fibrosis, but it only provides information on a small fraction of the kidney and due to their invasiveness cannot be repeated frequently and hence longitudinal monitoring is impossible. Using elastin-specific magnetic resonance imaging and collagen-specific optical imaging, we recently provided proof-of-concept for the non-invasive and quantitative assessment of whole organ kidney fibrosis stage, progression and anti-fibrotic treatment efficacy. This was done in multiple animal models of kidney fibrosis. In the present project, we will set out to further develop fibrosis-specific molecular imaging probes and protocols to non-invasively visualize and quantify renal fibrosis. We will focus on radionuclide-labeled probes for single photon emission computed tomography (SPECT) and on protocols that allow for direct translation to patients. The imaging agents that will be employed include ESMA and CNA-35 for capturing the extracellular matrix (ECM) components elastin and collagen, as well as BiPPB and FAPI for targeting the Platelet-Derived-Growth-Factor Receptor-beta (PDGFR-ß) and the Fibroblast Activation Protein (FAP). Among the key objectives of our project is the establishment of molecular imaging setups enabling the simultaneous assessment of both the ECM components and the cells that produce them (i.e. fibroblasts expressing PDGFR-β and FAP), which can be achieved by labeling our probes with radionuclides displaying distinct emission spectra. This dual-isotope SPECT setup is hypothesized to be valuable for providing differential diagnostic information on the transition of renal disease from initial injury to fibrosis and CKD, as well as on the differentiation between potentially reversible (and thus druggable) disease stages versus paucicellular and ECM-rich renal fibrosis, which is irreversible. Together, the diagnostic probes and protocols that will be developed in this project will contribute to the generation of novel disease-specific surrogate end-points, which will facilitate clinical drug testing and translational research, and which will improve patient management in CKD.
DFG Programme
Clinical Research Units
