From networks to mechanism in health and disease

1 PhD projects offered in the IPP winter call 2020/2021

Prediction and experimental validation of molecular mechanisms that underlie brain-specific phenotypes of NDDs

Scientific Background

More than 1000 Mendelian diseases are known that show disease manifestation in only one tissue. This tissue specificity seems surprising given that every cell of an affected individual carries the disease mutation. This tissue-specific phenotype could be explained by the mutated gene being only expressed in the affected tissue. However, this was only found to be the case for 20% of these diseases. Among the other 80% are neurodevelopmental disorders (NDDs), which comprise syndromes such as intellectual disability, developmental delay, autistic behaviour, and epilepsy. Mutations that have been associated with NDDs are primarily protein-coding but the molecular mechanisms underlying the brain-specific phenotype of NDDs remain largely unknown. Myself and others have hypothesized that tissue-specific phenotypes can also be caused by perturbation of an interaction between a broadly expressed “disease gene” and a tissue-specifically expressed interaction partner. However, brain-specific protein-protein interaction data are very sparse due to the difficulties in determining protein interactions endogenously at higher throughput.

PhD Project

Myself and others have shown that the cellular context of protein interactions, which were determined in an exogenous expression system, can be inferred via integration of protein interactions with gene and protein expression data. This has allowed to successfully explore cellular context-specific functions of proteins. The aim of the project is to further refine approaches for cellular context-specific protein interaction network inference using available tissue, cell type and single cell RNAseq and proteome data of the human and mouse brain on one side, and recently generated proteome-scale human protein interaction resources on the other. These approaches will be applied to predict potential molecular mechanisms that mediate the brain specific functions of NDD-related proteins. Furthermore, available genomic variation data and protein interaction interface information will be used to investigate whether known pathogenic mutations of NDDs are likely to disrupt the predicted brain-specific molecular mechanisms. Predicted mechanisms will be tested in vitro within the lab and with collaborators in neuronal cell models.

The PhD candidate will join a young, highly dynamic, and interdisciplinary research lab. The applicant should ideally have basic expertise in programming and statistics as well as in molecular biology techniques and a strong interest in integrative, data-driven systems approaches to biology.

Publications relevant to this project

Luck K, Kim DK, Lambourne L, et al. (2020) A reference map of the human binary protein interactome. Nature, 580(7803):402-408.

Luck K, Sheynkman GM, Zhang I, Vidal M (2017) Proteome-Scale Human Interactomics. Trends Biochem Sci, 42(5):342-354.

Yadav A, Vidal M, Luck K (2020) Precision medicine - networks to the rescue. Curr Opin Biotechnol, 63:177-189.

 

A 2nd PhD project "Elucidation of the molecular mechanisms regulating protein homeostasis by liquid-liquid phase separation" has been withdrawn.
 

Contact

Dr Katja Luck

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