Regulatory dynamics of network architecture and function in tristable genetic circuit of Leishmania: a mathematical biology approach.
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'.
a National Centre for Cell Science, NCCS Complex , Pune University Campus , Ganeshkhind, Pune 411007 , India.
Vineetha
V
Mandlik
a National Centre for Cell Science, NCCS Complex , Pune University Campus , Ganeshkhind, Pune 411007 , India.
Mayuri
M
Gurav
a National Centre for Cell Science, NCCS Complex , Pune University Campus , Ganeshkhind, Pune 411007 , India.
Shailza
S
Singh
D000465:Algorithms; D000981:Antiprotozoal Agents / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic; D053263:Gene Regulatory Networks / Q000235:genetics*; D006602:Hexosyltransferases / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007891:Leishmania / Q000201:enzymology / Q000235:genetics*; D007896:Leishmaniasis / Q000235:genetics / Q000469:parasitology / Q000517:prevention & control; D008264:Macrophages / Q000378:metabolism / Q000469:parasitology; D053858:Metabolic Networks and Pathways / Q000235:genetics; D008957:Models, Genetic; D015800:Protozoan Proteins / Q000235:genetics* / Q000378:metabolism; D013107:Sphingolipids / Q000378:metabolism; D017855:Transferases (Other Substituted Phosphate Groups) / Q000235:genetics / Q000378:metabolism
D000981:Antiprotozoal Agents; D015800:Protozoan Proteins; D013107:Sphingolipids; D006602:Hexosyltransferases; C088714:phosphatidylinositol-ceramide phosphoinositol transferase; D017855:Transferases (Other Substituted Phosphate Groups); C070186:phosphatidylcholine-ceramide phosphocholine transferase
IPCS; Leishmaniasis; Pareto front; multistate attractor dynamics; phase plane diagram; probabilistic boolean network; quasi-potential landscape; steady state simulation; tristable circuit