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|Title:||Development of novel therapeutic approaches for the reduction of apolipoprotein B expression|
|Authors:||McLaughlin, Catherine Louise|
|Presented at:||University of Leicester|
|Abstract:||Atherosclerosis is a chronic inflammatory disease of the arteries that represents the root cause of the majority of myocardial infarctions and strokes. The entry and accumulation of lipid particles, namely low density lipoprotein (LDL) particles, in the intima of the artery wall is a key step in the development of atherosclerotic lesions. Apolipoprotein B100 is the principal protein covering LDL particles and is necessary for their production by the liver. Currently, the most widely prescribed lipid lowering drugs are statins, which achieve only up to ~30% reduction of circulating LDL and are not suitable for all patients due to undesirable side effects; therefore novel means of LDL reduction are desirable. Pyrrole-imidazole polyamides are minor groove DNA binders with the potential to inhibit gene expression by binding in place of transcription factors in genetic promoter regions. In this project, small hairpin and a novel form of long linear polyamides, were synthesised to bind to the APOB proximal promoter and their effect on HepG2 hepatocyte expression of APOB and toxicity was investigated. Although polyamides successfully entered the cell nucleus, they did not inhibit APOB transcription. A library of natural product extracts was then screened to identify extracts which inhibited APOB promoter activity. Four extracts with such activity were identified and one with low toxicity was fractionated using liquid chromatography in an attempt to purify key active molecules that could be used as the basis for a novel therapeutic. Taken together, the results of this study have identified some limitations of polyamide technology, but also a number of natural product extracts which may have potential as leads for the development of future therapeutics for hyperlipidemia and related diseases including atherosclerosis.|
|Rights:||Copyright © the author. All rights reserved.|
|Appears in Collections:||Theses, Dept. of Cardiovascular Sciences|
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