Signalling Molecules in Neurons
Neural stem cells (NSCs) and progenitor cells (NPCs) possess great promise as therapeutic tools in neurological disorders such as the neurodegenerative diseases Parkinson’s disease (PD) and Huntington’s disease (HD), cerebrovascular diseases (stroke), neurotraumata (spinal cord injury) and demyelinating diseases (multiple sclerosis). The commitment of NSCs/NPCs to differentiate and mature involves complex events leading to the generation of different phenotypes via distinctive developmental programs. These regulatory changes can be influenced by small molecules affecting different steps of signalling pathways. For the fate of ventral midbrain NPCs, which are impaired in PD, Wnt pathways are of special importance. Several protein interactions, phosphorylation and dephosphorylation reactions and feedback regulations within the Wnt pathways are critically dependent on time delays, which can be simulated by dynamic mathematical modelling. It is a major aim of our research program to investigate the influence of new drugs on the β-catenin.dependent canonical Wnt pathway and dopaminergic differentiation in NCS/NPC lines in vitro with the help of:-protein analysis by quantitative Western blotting, immunofluorescence and flow cytometry
-analysis of transcriptional activity by quantitative real-time RT-PCR and reporter gene systems based on luciferase and enhanced green fluorescence protein (eGFP) induction
-testing of clinically relevant prototype small molecules and of combinatory chemical libraries by high-throughput screening (HTS) within cooperative projects and
-computational modelling and simulation within cooperative projects and testing of predictions of the model calculations.
Newly identified hit molecules will be tested in high content biochemical marker and functional assay systems, i.e. highly potent signalling pathway modifying small molecules identified by the HTS process will be assessed in vivo for enhancing of dopaminergic neurogenesis and improving locomotor performance in animal models of the neurodegeneration in PD. This will enable to transfer results to pre-clinical practice.
In addition, the erythropoietin (EPO) and a disintegrin and metalloproteases (ADAMs) are investigated for their role in developmental and repair processes of the central nervous system.