ERASMUS MC

The intestinal epithelium is the first line of defence of the mucosal immune system because it acts as a dynamic physical barrier segregating the luminal content from the underlying mucosal tissue. This barrier is mainly formed by a monolayer of specialised intestinal epithelial cells (IECs) that are crucial in maintaining intestinal homeostasis. Damage to this epithelial layer can increase intestinal permeability and lead to abnormalities in interactions between IECs, stromal cells and immune cells in the underlying lamina propria thereby disturbing the intestinal immune homeostasis, all of which are a hallmark of several intestinal disorders including inflammatory bowel diseases (IBD). Ulcerative colitis (UC) and Crohn’s disease (CD) are the two major forms of IBD, affecting an estimated 4 million people in the United States and Europe and have a rising incidence in the developing world. Recent single cell RNA seq (scRNAseq) studies of the intestine have allowed us to understand this organ in unprecedented detail, however, such studies still require the dissociation of tissue and loss of spatial resolution. With this project, I would like to take advantage of recent advances in in-situ sequencing to study intestinal tissue in toto and by combining this with the available scRNA-seq data, generate spatial maps of the intestine (GUTMAPS). The results obtained here will allow us to look at tissue composition and cell-cell interactions with unprecedented resolution in normal and diseased mucosa.

Provision of safe water is vital to ensure the stability and function of society and overall public health. The WHO estimates that 2 billion people still drink contaminated water, and lack access to safe sanitation. While the burden of waterborne diseases is disproportionally higher in poorer countries, the safety of our water supply is challenged everywhere by rapid world population growth and climate change, testing the capacity of sewage treatment systems and resulting in increasing environmental pollution. Therefore, effective removal and inactivation of viral pathogens during wastewater treatment is a global issue. Diseases due to consuming contaminated water are preventable and the resulting deaths can be avoided. Safe reuse of wastewater requires efficient inactivation of mammalian pathogens in the treatment process, especially emerging pathogenic viruses however current methods are established for bacteria and protozoa; far less is done for viruses due to greater diversity and the challenges of growing human and animal viruses. Bacteriophages, viruses of bacteria, offer an alternative as surrogates for mammalian viruses. In this fellowship, I propose to develop better systems to monitor and assess virus inactivation methods during wastewater treatment, through two specific objectives: (1) Identification of ubiquitous endogenous phage as surrogates for human/animal pathogenic viruses in virus inactivation evaluation; and (2) Develop phage activity assays to measure and evaluate the virus inactivation efficacy of novel wastewater reuse treatment schemes. Through this fellowship, I will gain multi-disciplinary knowledge and enhance my skills in virology, bioinformatics, microbiology and water technology. These acquired competences and experience will broaden my skills as an independent researcher. The outputs of this research fellowship are expected to have global application as well as provide useful tools for improving wastewater management and water quality.

APOBEC mutagenesis is a cellular mechanism by which genetic alterations are acquired somatically, driven by APOBEC enzyme family members. This mechanism is prominently observed in 15% of primary and 25% of recurrent breast cancer, the most common cause of cancer-related death in middle-aged women. Current evidence suggests APOBEC mutagenesis contributes to all disease stages, i.e. cancer initiation, progression and treatment resistance. The core idea of the AMBER project is that unravelling the mechanism of APOBEC mutagenesis induction and maintenance will turn this mechanism into breast cancer’s Achilles heel. To prove this, I will answer several challenging research questions: Why is APOBEC mutagenesis operational in breast cancer? How does APOBEC contribute to disease progression? Can we target APOBEC mutagenesis or APOBEC driven tumours specifically? First, I will reveal epidemiological and molecular evidence for factors inducing APOBEC mutagenesis in breast cancer. This may help to prevent APOBEC mutagenesis from occurring, potentially decreasing breast cancer incidence. Second, using global and single cell genomics, I will secure a link between APOBEC mutagenesis and disease progression, giving leads to delay progression. Third, I will exploit a potential vulnerability of APOBEC driven breast cancer, since I have found that these tumors may depend on a proficient homologous DNA repair (HR) pathway. When experimentally confirmed, targeting HR may extinguish APOBEC driven disease. Finally, I have observed that APOBEC mutagenesis associates with a profound immune response. I hypothesize that this is due to a new type of neo-epitopes being produced. If proven true, targeting these neo-epitopes provide another effective means to eradicate APOBEC driven tumors. I am confident AMBER will provide the fundamental insights into APOBEC mutagenesis needed to turn it into an Achilles heel which may help to prevent, delay or cure APOBEC driven breast cancer.