Universiteit Leiden

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Animal Sciences & Health

Mechanisms of Disease

Understanding the molecular and cellular basis of health and disease and how environmental factors influence the manifestation of disease phenotypes is essential for developing improved strategies for disease prevention and treatment. The mechanisms underlying human diseases most often relate to biological processes that are strongly conserved through evolution, such as cell communication, signal transduction, metabolism, inflammation and immunity. These processes rely on interaction between multiple cell types, tissues and organs of the whole organism. Therefore, animal models of disease are invaluable tools to study the complexity of disease phenotypes.

Zebrafish as a biomedical research model

The zebrafish has rapidly gained ground as a model species in preclinical biomedical research. This is especially due to the highly efficient combination of genetic approaches, non-invasive bio-imaging, and high-throughput chemical screening that is possible in research using the early life stages (embryos and larvae) of the zebrafish. At the Institute of Biology Leiden we focus on zebrafish models for infectious diseases, inflammatory disorders, diabetes, and cancer. This work contributes to two research focus areas of Leiden University: "Bioscience, the science base of health" and “Translational drug discovery and development”.

Modeling of infection, inflammation, diabetes and cancer

We have developed zebrafish models for studying innate host defence mechanisms involved in several bacterial and fungal infectious diseases. Specifically, we focus on pathogen recognition pathways, the antimicrobial function of autophagy, and the chemokine signaling axes that determine migration and functional properties of the major phagocytic cell types, macrophages and neutrophils. The overall goal of these projects is to identify potential targets for novel host-directed therapies against infectious diseases, in particular tuberculosis.

Diabetes is known as a tuberculosis risk factor and our zebrafish models provide a new angle to address the connection between insulin resistance and impaired immune function. Using zebrafish inflammation and infection models, we also study the immune suppressive effects of glucocorticoid hormones as well as mechanisms of glucocorticoid resistance, which forms a major problem in treatment of inflammatory and autoimmune diseases.

Another important focus area is cancer biology. We have developed transgenic and xenograft models to study how cancer cells interact with their microenvironment during tumor progression, tissue invasion, and metastasis. The ultimate aim of this work is to establish zebrafish as a key model for rapid discovery and assessment of cancer genetic targets and drugs to develop strategies for cancer therapies.

Connections with other themes and research groups

Emerging research fields such as immunometabolism and neuroimmunity are at the crossroad of the three themes in the Animal Sciences & Health cluster. With the combined expertise of molecular and behavourial biologists we aim to gain a better understanding of how different individual personalities and coping styles affect disease susceptibility. Our zebrafish disease models are applied to screen natural products from various sources, including snake venoms and plant extracts, in collaboration with the Natural Products Lab. Together with the Microbial Biotechnology & Health cluster we aim to increase insight into host-pathogen interactions and development of resistance or tolerance to antibiotics. Bio-imaging of disease processes in zebrafish is spearheaded by the world-class facilities at the Cell Observatory and NeCEN. We collaborate with other institutes of the Faculty of Science on topics such as single-molecule microscopy of chemokine and steroid hormone receptors (LION), applications of chemical probes and nanodelivery systems (LIC), metabolic profiling and drug toxicity screening (LACDR), automated image analysis and computational modelling (LIACSMI), and ecotoxicology (CML). Furthermore, many of our projects are carried out in close collaboration with research groups at the LUMC and companies in the BioScience Park.

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