Phd ThesisThe mammalian Target of Rapamycin (mTOR)kinase is a central regulator of
cellular growth and metabolism and plays an important role in ageing and age-
related diseases. The increase of invitro data collected to extend our knowledge
on its regulation, and consequently improve drug intervention,has highlighted
the complexity of the mTOR network. This complexity is also aggravated by
the intrinsic time-dependent nature of cellular regulatory network cross-talks and
feedbacks. Systems biology constitutes a powerful tool for mathematically for-
malising biological networks and investigating such dynamical properties.
The present work discusses the development of three dynamical models of the
mTOR network. The first aimed at the analysis of the current literature-based
hypotheses of mTOR Complex2(mTORC2)regulation. For each hypothesis, the
model predicted specific differential dynamics which were systematically tested
by invitro experiments. Surprisingly, nocurrent hypothesis could explain the
data and a new hypothesis of mTORC2 activation was proposed.The second
model extended the previous one with an AMPK module. In this study AMPK
was reported to be activated by insulin. Using a hypothesis ranking approach
based on model goodness-of-fit, AMPK activity was insilico predicted and in
vitro tested to be activated by the insulin receptor substrate(IRS).Finally,the
last model linked mTOR with the oxidative stress response, mitochondrial reg-
ulation, DNA damage and FoxO transcription factors. This work provided the
characterisation of a dynamical mechanism to explain the state transition from
normal to senescent cells and their reversibility of the senescentphenotype.European Council 6FP
NoE LifeSpan, School of the
Faculty of Medical Sciences, Newcastle Universit
