A systems view of protein homeostasis
We study how cells maintain protein homeostasis through the integrated regulation of protein synthesis, folding, trafficking, and degradation pathways. Failure of protein homeostasis is linked to severe so-called “protein misfolding diseases” that include Alzheimer’s and Parkinson’s. A decline in protein homeostasis is associated with aging, and dysregulation of the protein homeostasis network is a common hallmark of tumorigenesis in all cancers.
Computational models that integrate mechanistic biochemical knowledge with large-scale systems biology datasets have proven tremendously fruitful for understanding complex cellular processes. We develop and apply computational and systems biology methodology to discover and dissect - across scales from the sequence to the network level - principles of successful protein homeostasis in health, and causes for failure or dysregulation of protein homeostasis in diseases.
From high-throughput to mechanistic insight
We apply computational and evolutionary approaches to extract novel biological insight and directly testable mechanistic hypotheses from complex genomic data. Of particular interest are the discovery and characterisation of regulatory principles that support proteome integrity. Current projects focus on mechanisms of transcription and translation regulation as well as regulatory functions of targeted protein quality control in maintaining protein homeostasis.
Reconstructing cellular networks from genomic data
We develop novel computational tools for the reconstruction, analysis, and constraints-based modeling of cellular networks. Through targeted perturbation and experimental validation we then aim to refine quantitative models of protein homeostasis systems. Next to providing innovative strategies for harnessing the power of genomic data, we anticipate these efforts to reveal fundamental insights into the functioning and organisation of the protein homeostasis network and its response to perturbations.
Targeting protein misfolding diseases
By applying our gained knowledge and developed framework to paradigms of ageing and neurodegeneration, we seek to discover novel data-driven strategies to detect and target protein misfolding diseases. We are particularly interested in identifying re-wiring events in the protein homeostasis network that may serve as biomarkers for the early onset of pathologies linked to protein homeostasis failure, as well as understand how re-direction of fluxes through the protein homeostasis network may allow the rational re-engineering of the underlying protein quality control systems for therapeutic intervention.