The aim of the previous project was to assess the role of the two transmembrane, receptor-like protein tyrosine phosphatases PTPRJ/DEP-1 and PTPRC/CD45 in regulating transformation of myeloid cells by the acute myeloid leukaemia (AML)-related oncoprotein FLT3-ITD in vivo. In addition to aberrant haematopoiesis, the inactivation of the Ptprc gene in FLT3-ITD mice resulted in a marked and unexpected bone phenotype. These data indicated a previously unrecognized role of FLT3 in regulation of bone metabolism, which is affected by Ptprc. The aim of this proposal is to unravel the mechanisms underlying the FLT3-ITD-Ptprc-mediated signalling axis to control bone formation and remodelling.
How does receptor dynamic influence ligand residence time and ligand efficacy at adenosine receptors
Ligand receptor interaction is often simply seen as a binding event and neglects the conformational dynamic of the target protein and its influence on ligand binding or the efficacy of the ligand. Within this project will measure conformational dynamic of a receptor and monitor ligand binding with high kinetic resolution in living cells. We will use a fluorescence-resonance-energy-transfer (FRET) based approach to measure ligand on/off-rates and receptor activation/deactivation in real-time to obtain ligand residence time information and ligand efficacy data in living cells.
Age-dependent protein modifications of the AMP-activated protein kinase (AMPK)
Posttranslational protein modifications (PTMs) of proteins represent molecular mechanisms, which may lead to age-dependent functional decline of cells and tissues. The current project investigates modifications of AMPK, an important metabolic sensor and regulator enzyme, in vascular endothelial cells. We propose that PTMs of AMPK and AMPK-regulating enzymes lead to endothelial dysfunction thereby supporting the development of age-associated vascular diseases. The aim of this work is to identify these PTMS and to characterize AMPK as a pharmacological target to protect from vascular ageing.
Mechanisms mediating the balance of resistance and tolerance responses of the host to infectious stress are largely unknown. Preliminary data disclose PI3Kg as a mediator of memory-like adaptive responses in microglia. The current approach intends to clarify PI3Kg -related signaling processes involved in microglial adaptive responses controlling trained sensitization and tolerance. Aim of this approach is to decipher whether or not these microglial adaptive responses are able to ensure a specific impact on inflammatory preconditioning in focal brain ischemia.
Schwann-cell tumors (SCT) are benign tumors of peripheral nerves. SCT grow non-invasively but displacing and disturb therefore the affected nerves. Until now, no specific therapy is available. Aim of this project is to perform a preclinical confirmatory study (PCS). This PCS is mandatory in order to verify that the intended translation of the novel rhNRGβ1 protein substitution therapy for SCT treatment in humans is accomplished on a secured scientific basis.
Oncornet 2.0 – Oncogenic Receptor Network of Excellence and Training
Conformational signature of CXCR4/ACKR3 activation in β-arrestin-1 and -2
Our current knowledge is very limitted with respect to GPCR/arrestin interaction and the role of individual GRKs in this process. Most of the GPCR-family members are regulated by only four of the seven members of the GRK-family (namely GRK 2,-3,-5, and -6) and two of the four arrestin proteins that exist in human physiology, namely β-arrestin 1 and β-arrestin 2. For this system of GPCR regulation to be conceivable, β-arrestins require the ability to adopt to a multitude of different receptor activation and phosphorylation states, supposedly facilitated by a high degree of conformational plasticity within β-arrestin.
A large equipment application with ERDF funding was approved, so that a Leica SP8 laser scanning confocal microscope with four detectors and a Lightning module for resolutions up to 150 nm in living cells could be purchased in 2019 .