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Title: Development of novel synthetic and systems biology tools for investigating and obviating the effect of atherogenic blood flow on vascular cells
Author: Kis, Zoltan
ISNI:       0000 0004 5918 4289
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2014
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The high mortality from cardiovascular diseases is caused by atherosclerosis. Atherosclerosis develops due to multiple factors, including biomechanical factors, such as shear stress generated by the flow of blood on the inner lining of blood vessels. In order to tackle this serious life-threatening condition, we aimed to develop synthetic and systems biology tools for studying the effect of atherogenic shear stress regimes on vascular cells. Our tools could potentially also lead to the identification of drug targets and of drug candidates against cardiovascular disease. The first tool that we developed is a network of genes consisting of a shear stress sensor module, a reporter module and a linker module which signals from the sensor to the reporter module. This circuit is capable of processing the shear stress or ligand activation signal into a fluorescent readout, allowing screening for drug candidate compounds that modify the activity of the shear stress sensor. Instead of the reporter module, the gene network could be coupled to therapeutic genes in order to express these genes under atherogenic shear stress conditions. Our second developed tool is a flow chamber which facilitates exposure of vascular cells to linearly increasing shear stress along the length of the channel floor for in vitro cellular biomechanical studies. This device outperforms currently available linear shear stress inducing devices in terms of the magnitude of shear stress range, linearity of shear stress along the channel length, and the large sampling area granted by the uniformity of shear stress across the channel width. The third tool that we developed is an electroporation and flow device capable of inserting genetic material into primary vascular cells in their adherent state, exposing these cells to fluid flow. This device allows investigations into cardiovascular mechanotransduction pathways under relevant physiological flow conditions.
Supervisor: Krams, Rob Sponsor: Imperial College London
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available