Student projects at the Paul Scherrer Institut

In vitro tumor therapy using radioactive folic acid conjugates
Our group is focusing on the development, evaluation and application of folate-based radiopharmaceuticals useful for targeting folate receptor (FR)-positive tumor cells for imaging purposes and potential therapy. The aim of the project will be to establish in vitro therapy assays (e.g. MTT assay) that will be used to test the effect of folate conjugates radiolabeled with particle-emitting radionuclides (¹⁷⁷Lu β^-), ⁶⁷Cu (β^-), ²¹³Bi (α)) alone and in combination with chemotherapeutics such as e.g. antifolates.
Contact person: Cristina Müller

Radiolabeled antibodies for tumor diagnostics and therapy
The focus of our research group is the development of radiolabeled antibody-based drugs. We offer student projects which include screening for novel antibodies and tumor targets, the biological characterisation of tumor-specific antibodies, and antibody engineering (recombinant DNA technology or chemical functionalisation). We encourage students which are interested in working in an interdisciplinary environment to contact us for further details.
Contact person: Eliane Fischer or Jürgen Grünberg

Structure-function studies of neuropilin interactions
Neuropilins (Nrps) are a vertebrate-specific family of transmembrane glycoproteins that are crucial for the embryonic development of neural and vascular systems. In the adult organism they are implicated in many processes, such as angiogenesis and the immune response. Moreover, Nrps are highly expressed in numerous types of tumors, which results in higher microvessel density and correlates with diminished survival and poor prognosis. Nrps bind several members of the semaphorin family, as well as angiogenesis factors of the vascular endothelial growth factor (VEGF) family and a wide range of other growth factors and cell surface receptors, such as plexins, VEGF receptors or the neural cell adhesion molecule L1 (L1 CAM). The goal of our research is to explore the molecular interactions underlying receptor activation and signaling mediated by VEGFs and semaphorins through both the Nrp/VEGFR and the Nrp/Plexin receptor complexes. We use X-ray crystallography in combination with electron microscopy and biochemical experiments to provide a detailed view of these interactions and contribute to the understanding of the molecular mechanisms of receptor activation. The thesis work will comprise expression, purification, characterization and crystallization of selected target fragments.
Contact person: Andrea Prota

Analysis of the endosomal sorting of activated receptor tyrosine kinases
Receptor tyrosine kinases are activated by the binding of their matching growth factors. Activation leads to posttranslational modifications (phosphorylation, ubiquitination) and internalization of the receptor. In the endosomal compartment, the activated receptor is either classified for signaling, recycling, or degradation.
We want to study this process with time lapse microscopy. Therefore we developed a vector system that allows the expression of several fluorescently labeled proteins within a cell. This project focuses on the influence of myotubularins on the sorting of the EGFR and VEGFR.
Contact: Philipp Berger

Intracellular Trafficking of Serotonin Receptor 5HT2c and its Consequences for Receptor Signaling
The serotonin (5HT) receptors are rhodopsin-like G protein-coupled receptors (GPCRs) which are mainly found in the central and peripheral nervous systems. The serotonin receptors are activated by serotonin and various pharmaceutical drugs, thereby modulating neurological processes via association with heterotrimeric G-proteins. Signaling by GPCRs does not only depend on the interaction with G-proteins, but it also requires the cross-talk with other signaling pathways following ligand-induced receptor internalization.

GPCR signaling and trafficking studies performed so far have been carried out only with distinct intracellular vesicle types and signaling pathways. We want to draw a systematic road map of the intracellular trafficking routes of serotonin receptors upon stimulation with specific ligands. We then will correlate receptor trafficking among different vesicular compartments with signal output generated by a particular receptor.

We will use Rab GTPases as markers for intracellular vesicular receptor trafficking since their roles in endocytosis, recycling, and degradation are well studied. We will focus on the 5-HT2c receptor subtype and use Rab4, Rab5, Rab7 and Rab11 as vesicular markers. Co-localisation of the receptor with the different Rab compartments after stimulation with different agonists and antagonists will be quantified. Students become familiar with the cloning of expression constructs, cell culture techniques, fluorescent microscopy, and automated image analysis in this project.

Contact: Prof. Dr. Gebhard Schertler or Philipp Berger

Angiogenic signaling by receptor tyrosine kinases; the role of co-receptors in the activation of VEGF receptors
VEGF receptor tyrosine kinases regulate blood and lymphatic vessel development under normal and pathological conditions and are activated upon ligand-induced dimerization.We recently showed that the monomeric extracellular domain of VEGFR-2 has a flexible structure. Binding of VEGF to the membrane-distal domain caused receptor dimerization followed by drastic structural rearrangaments. By this mechanism ligand-induced dimerization of VEGFR-2 is communicated across the membrane, activating the intracellular tyrosine kinase domain. The specificity of VEGFR-2 signaling depends on co-receptors of the neuropilin family. Some VEGF variants bind both VEGFR-2 and neuropilin while others only bind VEGFR-2. In this project we will further characterize the downstream signaling components activated by VEGFR-2 upon binding to distinct VEGF isoforms in the presence and absence of neuropilin. We will also determine the biological output generated by the different VEGF isoforms. The results of this project have clinical implications in that the various VEGF isoforms elicit different signal output resulting in changes in vessel permeability, vessel maintenance or proliferation depending on the specific VEGF variants expressed in a particular tissue.
Contact: K. Ballmer-Hofer