SPEAKER
Prof Boris KHOLODENKO
Professor of Systems Biology, Deputy
Director of Systems Biology Ireland (SBI),
Conway Institute Member, University
College Dublin, Ireland
Professor Adjunct of Pharmacology,
Department of Pharmacology, Yale
University School of Medicine,
New Haven, USA
HOST:
LIH
RESPONSIBLE LIH SCIENTISTS:
Feng He
(feng.he@lih.lu)
www.lih.lu
www.uni.lu
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GETTING INSIGHTS INTO CELL BIOLOGY BY NETWORK
RECONSTRUCTION AND MODELLING
ABSTRACT
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Omics technologies have generated large
inventories of genes, transcripts, proteins,
and metabolites. The challenge is to find
out how they work together to regulate
cellular responses to external and internal
cues. Computational models provide insight
into the intricate relationships between
stimuli and cellular responses. I first
overview a suite of physics-based methods,
known as Modular Response Analysis,
which infer both direct causative connections
and their strengths in cellular signaling
and gene networks from perturbation data
(https://www.ncbi.nlm.nih.gov/pubmed/12242336).
Further, I show that drug resistance resulting
from dimerization of kinases (such as,
BRAF/CRAF, JAK2, etc) can be explained by
allosteric inhibitor effects and the emergence
of different drug affinities between
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free kinase monomers versus dimers
(https://www.ncbi.nlm.nih.gov/pubmed/26344764).
Finally, I overview an exciting and counterintuitive
discovery made using a new type
of mathematical modelling, which combines
aspects of protein structure, posttranslational
modifications, thermodynamics,
and dynamic reaction mechanisms
(https://www.ncbi.nlm.nih.gov/pubmed/30007540).
We used model predictions to block oncogenic
RAS signalling in metastatic melanoma
cells. RAS is mutated in 30% of all human
cancers, and RAS mutated cancers are clinically
considered to be undruggable and
resistant to current treatments. Our approach
identified non-intuitive drug combinations
that synergise to block critical RAS
effector pathways.
Website: http://www.ucd.ie/sbi/
https://people.ucd.ie/search/Kholodenko
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