Regulatory dynamics of network architecture and function in tristable genetic circuit of Leishmania: a mathematical biology approach

Abstract

The emerging field of synthetic biology has led to the design of tailor-made synthetic circuits for several therapeutic applications. Biological networks can be reprogramed by designing synthetic circuits that modulate the expression of target proteins. IPCS (inositol phosphorylceramide synthase) has been an attractive target in the sphingolipid metabolism of the parasite Leishmania. In this study, we have constructed a tristable circuit for the IPCS protein. The circuit has been validated and its long-term behavior has been assessed. The robustness and evolvability of the circuit has been estimated using evolutionary algorithms. The tristable synthetic circuit has been specifically designed to improve the rate of production of phosphatidylcholine: ceramide cholinephosphotransferase 4 (SLS4 protein). Site-specific delivery of the circuit into the parasite-infected macrophages could serve as a possible therapeutic intervention of the infectious disease ‘Leishmaniasis’.

Keywords:

• Leishmaniasis
• IPCS
• tristable circuit
• steady state simulation
• probabilistic boolean network
• phase plane diagram
• quasi-potential landscape
• multistate attractor dynamics
• Pareto front

Acknowledgments

The authors would like to thank the Director, National Centre for Cell Science (NCCS), Pune, for supporting the Bioinformatics and High Performance Computing Facility. Vineetha Mandlik acknowledges the financial support as Senior Research Fellow of Department of Biotechnology, Government of India.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was supported by Department of Science and Technology, Ministry of Science and Technology, Government of India [grant number SB/FT/LS400/2012].