The inside of the human gut is covered with a thick layer of sugar molecules. This layer is hard to access, making research into its biological role difficult. Mini-guts with a controllable sugar layer will be developed, to study the functions of sugars in normal gut development, colitis and cancer.

As our genome is constantly attacked by damage, DNA repair mechanisms are crucial to maintain genomic integrity and prevent cancer. A particularly harmful type of damage is a DNA interstrand crosslink (ICL), which covalently links the two strands of the double helix, forming a roadblock to all processes that involve DNA unwinding. ICLs are formed by endogenous processes and high doses of ICLs are used in cancer therapy. The repair of ICLs involves several different repair pathways but little is known about its biochemical mechanism. Especially the role of the Fanconi anemia pathway in ICL repair has remained enigmatic. Fanconi anemia is a genetic cancer predisposition disorder caused by mutations in any of the thirteen FANC genes. The FANC proteins confer resistance to ICLs but their role in ICL repair is unclear. We have developed a Xenopus egg extract-based system that enables the efficient repair of a site-specific ICL in vitro. I have used this system to show that the FA pathway is crucial for ICL repair, and that two different steps in this process are blocked when the FA pathway is compromised. These steps are the incisions that unhook the crosslink and translesion DNA synthesis beyond the crosslink. Now, I will take another step in deciphering the molecular mechanism of ICL repair by answering the following questions: 1) Which endonucleases perform the incisions that unhook the ICL, and are these two incisions coupled? 2) Does the FA pathway directly regulate the incisions, and if so, how? 3) Are novel proteins involved in ICL repair and what is their role? This will provide insights in one of the least understood DNA repair pathways and may improve the use of cancer therapy. In addition, functional data on the Fanconi anemia pathway is important in the progress towards therapies for Fanconi patients.

Wnts are secreted signaling proteins that play a central role in development, adult tissue homeostasis and cancer. In the past decade, detailed insight has been gained into the signaling pathways that are triggered by Wnts, but how Wnts are secreted from producing cells and how this process is regulated to control signaling activity is still largely unexplored. Recent studies have shown that Wnt secretion is mediated by a dedicated secretory pathway. A central player in this pathway is the Wnt binding protein Wntless (Wls), which transports Wnt from the Golgi to the cell surface for release. Because Wls is a limiting component in the pathway, it needs to be recycled back to the Golgi to maintain Wnt secretion. We have shown that this is mediated by the retromer, a multi-subunit trafficking complex that transports endocytosed Wls from endosomes to the trans-Golgi network (TGN). Importantly, we recently found that Wls retrieval requires a novel, SNX3-dependent retromer pathway that segregates Wls into vesicular carriers that are morphologically distinct from the tubular transport carriers that are formed by the classical retromer pathway. To gain further mechanistic insight into this key step in the Wnt secretion pathway, we will investigate how these vesicular carriers are formed, how they dock at the TGN and how Wls is specifically sorted into this novel transport pathway. Detailed insight into this mechanism will contribute to our understanding of the Wnt secretion pathway and will identify potential new drug targets for the therapeutic inhibition of Wnt secretion in cancer.

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.

SCADA and ICS formerly relied on isolated systems and proprietary protocols, but are increasingly interconnected and employ open protocols or protocols encapsulated in TCP/IP. From smart grids to advanced automated manufacturing, these trends provide opportunity for vastly increased system performance, but may also expose these systems to cyber-attacks. The situation is exacerbated in that, enterprise security practices do not always transfer well to SCADA and ICS. However, these systems are also characterized by regular communication patterns and relatively simple protocols. Investigated is whether intrusion detection techniques that are not widely used in business systems can be applied in these environments.