Research: 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.