The aim of the research described in this thesis entitled ‘The use of transcriptomics data in detecting non-genotoxic carcinogens’ was to develop in vitro tests to improve testing strategies for... Show moreThe aim of the research described in this thesis entitled ‘The use of transcriptomics data in detecting non-genotoxic carcinogens’ was to develop in vitro tests to improve testing strategies for cancer hazard assessment of chemicals, to reduce the use of in vivo experiments. The scope of this thesis was twofold. First, an improved in vitro approach to assess genotoxicity was developed, with the intention to reduce the number of misleading positive test results. The emphasis was on characterization of the cell system, primary hepatocytes derived from transgenic mice. Results showed that this cell system will be of added value in genotoxicity testing. In the second part of this thesis, the focus was on the development of a ‘trancriptomics’-based approach to detect modes of action of non-genotoxic carcinogens. It has been demonstrated that the described comparison approach is promising in recognizing gene expression patterns, which can be related to modes of action. In addition, the approach is also suitable to detect toxicity of chemicals in general. In conclusion, through the development of in vitro approaches, as described within this thesis, an important contribution in the improvement of testing strategies for cancer hazard assessment of chemicals has been delivered. Show less
The aim of this thesis was to identify in the human blood transcriptome, relevant pathways and potential biomarker profiles that associate with chronological age and discriminate between __healthy... Show moreThe aim of this thesis was to identify in the human blood transcriptome, relevant pathways and potential biomarker profiles that associate with chronological age and discriminate between __healthy agers__ from long-lived families and normative ageing controls. Such profiles may harbor determinants of the biological ageing rate. We studied genome-wide gene expression profiles in blood of members of the Leiden Longevity Study (LLS) and replicated our findings by extended sampling within the unique LLS cohort. The findings of the exploratory analysis prompted us to investigate multiple genes in the IL7R and MTOR pathways for association with familial longevity. The results obtained by examining mRNA from blood samples brought us to study mTOR protein levels and signalling in primary skin fibroblasts from the corresponding donors in the LLS. Finally, to discover robust, biologically relevant gene networks as markers of chronological ageing in larger sample sizes, we performed an explorative network-based meta-analysis on large publicly available transcriptomic datasets. We have identified several networks, pathways and candidate genes potentially marking the biological age and the rate of ageing Show less
This dissertation mainly focuses on interdisciplinary approaches for biomedical knowledge discovery. This required special efforts in developing systematic strategies to integrate various data... Show moreThis dissertation mainly focuses on interdisciplinary approaches for biomedical knowledge discovery. This required special efforts in developing systematic strategies to integrate various data sources and techniques, leading to improved discovery of mechanistic insights on human diseases. Chapter one looks at the possibility in which combining various bioinformatics-based strategies can significantly improve the characterization of the OPMD mouse model. We discuss that this approach in knowledge discovery, on the basis of our extensive analysis, helped us to shed some light on how this model system relates to OPMD pathophysiology in human. In Chapter two, we expand on this combinatory approach by conducting a cross-species data analysis. In this study, we have looked for common patterns that emerge by assessing the transcriptome data from three OPMD model systems and patients. This strategy led to unravelling the most prominent molecular pathway involved in OPMD pathology. The third chapter achieves a similar goal to identify similar molecular and pathophysiological features between OPMD and the common process of skeletal muscle ageing. Engaging in a study in which the focus was made on the universality of biological processes, in the light of evolutionary mechanisms and common functional features, led to novel discoveries. This work helped us uncover remarkable insights on molecular mechanisms of ageing muscles and protein aggregation. Chapters four and five take a different route by tackling the field of computational biology. These chapters aim to extend network inference by providing novel strategies for the exploitation and integration of multiple data sources. We show that these developments allow us to infer more robust regulatory mechanisms to be identified while translations and predictions are made across very different datasets, platforms, and organisms. Finally, the dissertation is concluded by providing an outlook on ways the field of systems biology can evolve in order to offer enhanced, diversified and robust strategies for knowledge discovery. Show less
