EXCEED THE SPACE PROVIDED. The robust bistable geneticswitchplaysa pivotalroleincontrollingthe entryof a cellintoalternative developmentalstates,inthe stable maintenanceof thechosenstate,and in theswitchingfromonestable stateto the alternativestablestate. Thisresearchprojectexpectsto establishthe importantparameters underpinningtheoperationof the switch,bythe comparativeanalysisof three nativegeneticswitches. These switchescontrolthe alternativestatesof lyticresponseand lysogenyavailableto a temperate bacteriophage,a systemthat is experimentallytractable. In particular,the studyaimsto establishand comparativelyanalysethe roleof thesecondrepressor,the anti-immunerepressor,inthe operationof the isolatedbistableswitchinthe contextof thegeneticnetworkunderpinningphage development. Understandingthe operationof geneticswitchesis of fundamentalsignificanceto the researchprograms concernedwiththe reprogrammingof donorcellsfor cell-basedtherapyinthe 'new'medicineand to the developmentof geneticconstructsthatwilldelivertherapeuticsto a patientperiodicallyor onqueue. Simple geneticswitchesare alreadyinuse in thebiotechnologyindustryfor the commercialproductionof biopharmaceuticals.Finally,a betterunderstandingof the operationof the geneticswitchof temperate bacteriophages could be of potential significance in the treatmentof bacterial disease, as the pathogenesis of many bacteria is due to the phage that they carry in their genome. Our approach is to make mutations that selectively abolish the activity of the anti-immune repressor in each switch and then to examine the effect of these mutations at three levels: (1) on bacteriophage development, (2) on the behaviour of the bistable switch in the absence of other phage genes, and (3) on the autoregulatory gene control circuit that creates the switch. This will provide a coherent picture of how switches are achieved and how they are utilised within genomic networks. PERFORMANCE SITE ========================================Section End===========================================
