Gene expression thesis

differential gene expression

One of the large environmental changes in Iceland during the 19th century was in the diet of Icelanders, before the 19th century the Icelandic diet could be roughly classified as a ketogenic diet.

We evaluated if the difference in the expression pattern of these genes could be a result of modified expression of miR and miRb in the carrier fibroblasts.

Rna seq thesis

These studies demonstrate that large animal models are highly valuable in the field of cardiovascular biology. These studies showed differential expression of genes in the different cardiovascular tissues, demonstrating transcriptional differences between these different tissues known to have different functions. In this project, I have developed a range of novel in vitro and in vivo tools to advance the study of cardiovascular disease. The in vitro calcification of primary rat, human, porcine and bovine aortic valve interstitial cells VICs is commonly employed to examine the mechanisms of CAVD. This raised the question whether epigenetic gene control, specifically histon acetylation, could be a factor in HCCAA pathogenesis. Further to this work, I studied the expression profiles of these key cardiovascular genes during development in the sheep from foetal to adult stages. Despite the currently expanding list of genes reported to be involved in a variety of cardiovascular-related diseases, including calcific aortic valve disease CAVD , the functions and associated pathways of these factors in both normal and pathological physiology have yet to be fully understood, such as at the transcriptomic level. Given the importance of this role, it is not surprising that there are countless regulatory mechanisms at the molecular, cellular and tissue levels that are required to support this functional system. HOXD10 encodes for a transcriptional factor and it was the most downregulated gene in untreated carrier fibroblasts. Perturbations in parts of this system are likely to lead to abnormalities, and thus give rise to cardiovascular-related diseases.

In this thesis, a genome-wide transcriptomic atlas of the healthy mammalian cardiovascular system was generated using the sheep as a large animal model. The function of the cardiovascular system is to supply nutrients including oxygen to the various cells, tissues and organs within the body, and remove waste products from them.

CAVD involves progressive valve leaflet thickening and severe calcification, resulting in impaired leaflet motion. One interesting cluster was highly expressed in the cardiac valves, and shared genes found in physiological bone development, such as bone morphogenetic protein 4 BMP4 , collagen type I alpha 2 COL1A2 , Sry homeobox 8 SOX8 and bone gamma-carboxyglutamate protein BGLAP , some of which have been implicated in vascular calcification. These studies demonstrate that large animal models are highly valuable in the field of cardiovascular biology. It is a complex network of various tissues and structures with unique functions. In addition, the role of extracellular nucleotides and their receptors P2 receptors , which have been previously shown to be important in bone and vascular calcification, were investigated using SAVICs in vitro. We evaluated if the difference in the expression pattern of these genes could be a result of modified expression of miR and miRb in the carrier fibroblasts. ACAN encodes for the proteoglycan aggrecan and it was the most up-regulated gene in untreated carrier fibroblasts. For example, the carrier cells had elevated expression of select ECM protein genes.

However, to date, no published studies have utilised cell lines to investigate this process Thus, in this project, I generated and evaluated the calcification potential of an immortalised cell line derived from sheep aortic VICs SAVICs.

These studies demonstrate that large animal models are highly valuable in the field of cardiovascular biology.

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A detailed study on the genealogies of HCCAA families has shown that in the beginning of the 19th century the life expectancy of HCCAA patients was around 65 years; however, at the beginning of the 20th century the average life expectancy of carriers had dropped drastically to about 30 years and this average has been consistent since then.

Through this work, I identified novel gene networks and detailed functional clustering of co-expressed genes with region-specific expression and specialised cardiovascular roles. The in vivo and in vitro experimental models described should facilitate detailed analysis of cardiovascular molecular biology and ultimately lead to therapies which will minimise the morbidity and mortality currently arising from cardiovascular pathology.

One interesting cluster was highly expressed in the cardiac valves, and shared genes found in physiological bone development, such as bone morphogenetic protein 4 BMP4collagen type I alpha 2 COL1A2Sry homeobox 8 SOX8 and bone gamma-carboxyglutamate protein BGLAPsome of which have been implicated in vascular calcification.

Gene expression thesis

One plausible explanation for this reduction is a gradual change in some environmental factors that began around and reached saturation around This raised the question whether epigenetic gene control, specifically histon acetylation, could be a factor in HCCAA pathogenesis.

For example, the carrier cells had elevated expression of select ECM protein genes. This novel large animal in vitro model of CAVD was demonstrated to calcify under high calcium and phosphate conditions.

Rna seq thesis

We evaluated if the difference in the expression pattern of these genes could be a result of modified expression of miR and miRb in the carrier fibroblasts. Perturbations in parts of this system are likely to lead to abnormalities, and thus give rise to cardiovascular-related diseases. In addition to amyloid accumulation in cerebral arteries there is also a significant deposition of extracellular matrix ECM proteins. Despite the currently expanding list of genes reported to be involved in a variety of cardiovascular-related diseases, including calcific aortic valve disease CAVD , the functions and associated pathways of these factors in both normal and pathological physiology have yet to be fully understood, such as at the transcriptomic level. HOXD10 encodes for a transcriptional factor and it was the most downregulated gene in untreated carrier fibroblasts. CAVD involves progressive valve leaflet thickening and severe calcification, resulting in impaired leaflet motion. ACAN encodes for the proteoglycan aggrecan and it was the most up-regulated gene in untreated carrier fibroblasts. In the ENPP1-edited animals, soft tissue calcification has been observed in the biallelic mutant and homozygous pigs. For example, the carrier cells had elevated expression of select ECM protein genes. This raised the question whether epigenetic gene control, specifically histon acetylation, could be a factor in HCCAA pathogenesis.

This atlas was generated using RNA-seq, with the aim of further understanding normal gene expression patterns in the context of the known physiology of healthy mammalian tissues.

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