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Variation in Interpersonal Response to Statin Drugs in Hypercholesterolemia

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dc.contributor.advisor Couch, Robin D.
dc.contributor.author Khan, Hameed A.
dc.creator Khan, Hameed A.
dc.date 2012-12-06
dc.date.accessioned 2013-02-12T18:39:59Z
dc.date.available NO_RESTRICTION en_US
dc.date.available 2013-02-12T18:39:59Z
dc.date.issued 2013-02-12
dc.identifier.uri http://hdl.handle.net/1920/8007
dc.description.abstract Cardiovascular disease (CVD) is ranked as the number one cause of mortality and morbidity worldwide. High blood cholesterol is the number one risk factor for CVD events. Statins class of drugs is the first-choice agents prescribed in medical treatment for lowering cholesterol. Statins inhibit 3-hydroxy-3-methlyglutaryl-coenzyme A (HMGCR), the rate limiting enzyme in the biochemical pathway leading to endogenous cholesterol synthesis. There is however significant inter‐individual variation in the magnitude of response to statin use. This variation in LDL‐cholesterol response to statin has been linked to several phenotypic parameters including diet; in addition, there has been an ongoing investigation into the genetic determinants of the response to statin therapy. Single nucleotide polymorphisms (SNPs) in several genes are linked to reduced efficacy of statin therapy. From pharmacogenomic investigations it has been deduced that 37 different genetic loci contribute to an individual’s response towards statin therapy, this includes the gene encoding HMGCR. It has been recently suggested that HMGCRv_1 is an alternatively spliced transcript of HMGCR which is conceptualized to be a catalytically active, statin‐resistant isoform of HMGCR. We did several expression analyses using pETDuet-1 vector in a host E. coli strain BL21 (DE3). Both wild type HMGCR expression and a coexpression involving a dual expression of wild type HMGCR and the hypothetical HMGCRv_1 were performed. The wild‐type enzyme was soluble and catalytically active in each case. HMGCRv_1 was however neither active nor soluble in the co‐expression vector. Based on structural analysis, it is possible that since residues involved in dimerization were missing in the conceptual HMGCRv_1 construct, subunits association for a functional enzyme formation could not be accomplished, and the expressed protein settles insloluble. The US Food and Drug Administration emphasizes appropriate diet with conventional statin drugs indicating that their combined effect reduces the risk of cardiovascular disease. We therefore propose that an inhibitor with high hepatoselectivity could potentially result in an improved therapeutic window. Bioprospecting has been the source of most of the active ingredients of medicines. To stress upon the use of appropriate diet along with the use of statins we screened for HMGCR inhibitors from dietary extracts. We avoided the use of brute‐force high throughput screening approaches which sometimes fail to detect important secondary compounds and agents that go undetected due to high velocity flow through techniques. The proposed method is cost effective and without the need of robotic devices in identifying lead compounds. en_US
dc.language.iso en en_US
dc.subject variation to statins response en_US
dc.subject HMGCR isoforms and hypercholesterolemia en_US
dc.subject Duet Vectors for co-expression en_US
dc.subject Screeing for HMGCR inhibitors en_US
dc.subject Regulating cholesterol synthesis en_US
dc.subject Use of Cobalt Column for Bioprospecting en_US
dc.title Variation in Interpersonal Response to Statin Drugs in Hypercholesterolemia en_US
dc.type Thesis en
thesis.degree.name Master of Science in Chemistry en_US
thesis.degree.level Master's en
thesis.degree.discipline Chemistry and Biochemistry en
thesis.degree.grantor George Mason University en


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