The aim of this proposal is to engineer a synthetic biological network for in vivo regular therapeutic delivery of insulin in a rhythm corresponding to normal nutrient uptake. To this end, we will engineer stable synthetic oscillator networks in yeast and mammalian systems able to express mRNA/protein levels with a pre-determined frequency and amplitude.
The synthetic oscillator network has to guarantee stable and synchronized oscillation in the cell population. The yeast system will be used as a test-bed for the synthetic biology design strategies developed in this project. In the context of the mammalian tissue, individual cellular oscillators have to be synchronized in order to fulfill the macroscopic function of an insulin delivery device. Hence, the engineering of the synthetic network involves additional inputs and outputs that enable resetting of the oscillators.
In view of therapeutic application, the desirable system would reset insulin oscillations synchronously with the circadian rhythm. Specifically, the synthetic oscillator in the mammalian system will be connected to circadian signals like PER1 and CRY. To achieve this aim, COBIOS brings together scientists from yeast and mammalian molecular biology, computer science, engineering and control theory. We will employ methods from systems dynamics and control theory to develop and implement modular control networks that enable oscillations in the networks they will be connected to.
In particular, we will address the problems of
- robustness of controller dynamics,
- suitable interfaces to the controlled networks, and
- mechanisms for regulation of the controller's dynamic characteristics (e.g. period and amplitude) through external signals that can be exogeneous (yeast system) or outputs of cellular signal processing (the circadian clock in mammalian system) at the levels of individual cells and tissues.
Call for proposal
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