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Functional genomics in the stroke-prone spontaneously hypertensive rat: genome wide and candidate gene analysis

Polke, James M. (2008) Functional genomics in the stroke-prone spontaneously hypertensive rat: genome wide and candidate gene analysis. PhD thesis, University of Glasgow.

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Abstract

The stroke-prone spontaneously hypertensive rat (SHRSP) is an inbred model of hypertension. Renal microarrays and functional genomic strategies investigated chromosome 2 candidate hypertension genes, focussing on the oxidative-stress defence gene, glutathione s-transferse mu type 1 (Gstm1). Ingenuity pathway analysis of renal microarrays in 5 and 16-week SHRSP, normotensive Wistar Kyoto (WKY) and chromosome 2 congenic rats identified differential expression of several glutathione cycling genes. The Gstm1 promoter was investigated by luciferase and Transfac bioinformatic analysis, implicating two polymorphism clusters and several transcription factors in reduced SHRSP Gstm1 expression. Recombinant adenoviruses expressing Gstm1 and short-hairpin RNA-interference sequences to reduce Gstm family expression were produced. In-vivo overexpression of Gstm1 did not improve endothelial nitric-oxide bioavailability in SHRSP carotid arteries. Bacterial artificial chromosome and linear expression constructs were purified for production of Gstm1 transgenic rats, putative transgenic rats were screened by PCR. The strategies developed in this project are an example of thorough functional genomic analysis in experimental hypertension research.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Keywords: Genetics of hypertension, Complex disease genetics, Functional genomics
Subjects: Q Science > QH Natural history > QH426 Genetics
Colleges/Schools: College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Supervisor's Name: Dominiczak, Prof Anna F and McBride, Dr Martin W
Date of Award: 2008
Depositing User: Dr James M Polke
Unique ID: glathesis:2008-258
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 20 Aug 2008
Last Modified: 10 Dec 2012 13:17
URI: http://theses.gla.ac.uk/id/eprint/258

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