May 2017 – Departmental researchers Dr. Iris Jonkers and Dr. Sasha Zhernakova have both been awarded 2017 Vidi grants! These awards from the Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO – The Netherlands Organisation for Scientific Research) provide €800,000 for excellent original research programs that can be used to fund up to five years of research. Dr. Jonkers will be using newly developed techniques to identify which single nucleotide polymorphisms truly play a causal role in immune mediated disease using celiac disease as a model. Dr. Zhernakova will characterize the breast milk microbiome and the role it plays in baby health in the LifeLines Next cohort of mother-baby pairs.
The breast milk microbiome: the missing link between mothers and their babies’ health
Dr. A. (Sasha) Zhernakova
Breast milk is one of the major sources of gut bacteria in the first months of life. The gut microbiome in babies is linked to maturation of the immune and metabolic systems and to long-term health effects. However, despite the importance of understanding this link, no wide-scale studies have been performed linking the breast milk microbiome, the maternal factors that control its composition, the development of babies’ gut microbiome and baby health.
The aim of this study is to determine the role of the breast milk microbiome in maturation of babies’ gut microbiome and in babies’ health by characterizing the microbiome composition of breast milk and identifying which maternal factors shape the breast milk microbiome. This will be achieved by determination of the microbiome composition of breast milk and its links to the nutritional composition of breast milk, identification of maternal factors that influence the breast milk microbiome (including genetics, delivery mode, metabolic parameters, diet, diseases and environmental factors) and identification of the links between the breast milk microbiome, the baby gut microbiome and baby health (including diseases, colic, allergies, etc.).
We will perform metagenomics sequencing and data analysis to characterize the breast milk microbiome in samples provided by the unique LifeLines-NEXT cohort, which also provides access to comprehensive measurements and phenotypes in 1500 mother-child pairs. Characterization of the breast milk microbiome will further our understanding of which environmental and maternal factors influence the development of the infant gut microbiome. Results of this project will provide insights into avenues for developing specific recommendations for optimizing breast milk composition by intervening with the maternal environment (e.g. through diet) and pave the way for development of new probiotics.
Small changes, big effects: Finding the regulators of immune-mediated disease
Dr. I.H. (Iris) Jonkers
Immune-mediated diseases (IMDs) are complex diseases with a large genetic component. While many single nucleotide polymorphisms (SNPs) have been associated with IMDs, it is unclear which of these SNPs affect disease etiology because most associated SNPs are statistically indistinguishable from truly causal SNPs. Identification of causal SNPs is further hampered by the fact that associated SNPs are nearly always located in the non-coding genome and therefore affect regulatory processes. Nonetheless, identifying the causal SNPs is crucial to understanding the molecular mechanism underlying complex disease. Therefore, I aim to identify causal SNPs, the non-coding regulatory regions they disturb, and their downstream effects in an IMD-specific context.
I will use a cost-effective reporter-based sequencing assay that measures the autonomous activity of regulatory regions and the SNPs within them. I will enrich DNA sequences containing putatively causal IMD-SNPs and test these in the major cell types involved in IMDs. Next, I will establish the exact disease-context in which these SNPs function by examining gene expression and regulatory profiles of biopsies from patients with Celiac Disease, the most prevalent IMD. Finally, to test the downstream effects of SNP-mediated disruption of regulatory regions in IMDs, I will mutate regulatory regions in IMD-related primary and model cell lines to measure the effects on gene expression.
The results of this research will pinpoint causal SNPs, establish the cell type and disease-specific context in which they exert downstream effects, and quantify their downstream effects. This research will reveal how small changes can cause big effects in complex disease and prioritize the best targets for treatment design.