|Title:||Functional studies of EPAS1 in athletic endurance performance|
|Publisher:||University of Sydney.|
Sydney Medical School.
Central Clinical School - RPAH
|Abstract:||Endothelial PAS domain protein 1 is encoded by the EPAS1 gene which functions as a master regulator of oxygen homeostasis and is involved in transcriptional activation in several hypoxic adaptive processes. Previous studies have provided evidence for an association between EPAS1 haplotypes and endurance performance in elite athletes. However, functional EPAS1 DNA variants that influence elite endurance performance remain unclear. We hypothesised that some EPAS1 DNA variants represented by different haplotypes (PT-MAX and PT-SS) are likely to show different responses to oxygen metabolism and so give insight into possible mechanisms that might provide a specific advantage for some athletes involved in endurance performance. In vitro cell culture using cell lines with the defined haplotypes were used for measuring EPAS1 expression. In silico analysis was undertaken to identify potential regulatory regions associated with different haplotypes. Next generation sequencing was used to look for rare functional SNPs in the 5’ flanking and intron 1 region of EPAS1. The results showed: i) A difference in EPAS1 expression in different haplotype cell lines, ii) hypoxia does not increase expression of EPAS1 at the transcriptional level, iii) MARP a potential non-coding transcript was identified but could not be shown to play a significant regulatory role in the EPAS1 response to hypoxia, iv) The 5’ flanking region and first intron of EPAS1 gene was shown to be hot spots for transcriptional activity and v) a rare variant (rs4035887 A>G) in the PT-MAX haplotype altered the binding site of transcription factors. The above findings demonstrate how DNA base changes can alter functional significance of a gene, and the EPAS1 gene is likely to play a significant role in elite athletic endurance performance.|
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|Rights and Permissions:||The author retains copyright of this thesis. It may only be used for the purposes of research and study. It must not be used for any other purposes and may not be transmitted or shared with others without prior permission.|
|Type of Work:||PhD Doctorate|
|Type of Publication:||Doctor of Philosophy Ph.D.|
|Appears in Collections:||Sydney Digital Theses (University of Sydney Access only)|
|LE Huong - Final Thesis.pdf||Thesis||8.13 MB||Adobe PDF|
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