With increasing age, people’s cognitive skills decline. How fast this occurs, differs among people and depends on a variety of factors. Whether having autism is a risk-factor for accelerated aging or a potential protective factor is unknown. In this project this will be tested and influential factors will be determined.

During cancer surgery, all tumor tissue must be radically removed. Unfortunately, it is often only after surgery that it becomes apparent that this was not successful. The patient must then be treated with radiation or undergo a second operation. For example, in breast cancer, the number of operations that are not radical can be up to 20%. We have now developed a method, SmartScan, that can see during the operation whether all tumor tissue has been properly removed. This makes additional treatments unnecessary. In this study we want to investigate how we can best bring SmartScan to the market.

In our bodies genes need to be activated at the right time and the right place. Many of these genes are activated by pieces of DNA that are located far away in the genome. The folding of our genome plays an important role in the correct regulation of these genes. We will investigate which factors are important in this process. This will lead to a better understanding how genes are regulated during embryonal development and what happens in developmental disorders.

The microtubule cytoskeleton is regulated by a group of microtubule associated proteins that are specifically targeted to growing microtubule plus ends. These protein are called plus-end tracking proteins or +TIPs. The highly conserved autonomous +TIP family of End Binding (EB) proteins controls the recruitment of most other +TIPs to microtubule ends and is a central regulator at microtubule ends. The interaction of EBs with microtubules and its partners is regulated by posttranslational phosphorylation events to control the multiple different functions microtubules have in the cell. In budding yeast the EB family is represented by the single homologue Bim1. Interestingly, in a proteomics screen for Bim1/EB1 binding partners several protein kinases were uncovered. Many of the kinases or their complex partners contain structural features observed in known Bim1/EB1 partners suggesting that they could represent novel Bim1/EB1 partners phospho-regulating microtubule function. Preliminary analysis of several kinases has confirmed the surprising interaction with Bim1/EB1. In addition, colocalization of microtubule tips with several kinases could be observed, and finally in vitro a purified kinase complex could phosphorylate recombinant +TIPs. The aim of this research proposal is to unravel the mechanistic and functional link between the microtubule plus ends and the identified kinases in budding yeast. I will determine the molecular mechanisms responsible for the interaction by generating mutant yeast strains and using purified proteins in vitro. I will study the temporal and spatial regulation of the interactions by cell cycle controlled experiments and fluorescent microscopy techniques. I aim to understand the cellular role of the interactions by studying microtubule dynamics, cell morphology and any cellular processes the kinases have previously been linked to, using mutant cells. Finally, I will determine if there is a level of conservation in higher eukaryotes by probing the interaction between +TIPs and the identified kinases in mammalian cells.