Vinsamlegast notið þetta auðkenni þegar þið vitnið til verksins eða tengið í það: http://hdl.handle.net/1946/22025
Hereditary Cystatin C amyloid Angiopathy (HCCAA) is a rare Icelandic genetic disease caused by a mutation in the cystatin C gene CST3, L68Q-CST3. The mutation results in accumulation of the mutant protein product as amyloid in various tissues, predominantly in cerebral arteries of patients causing their death from intracerebral hemorrhages. In addition to amyloid accumulation in cerebral arteries there is also a significant deposition of extracellular matrix (ECM) proteins. This is of interest for the pathology of the disease as ECM proteins have been implicated in “trapping” amyloid forming proteins and thus facilitating local amyloid formation. Previous unpublished data from microarray study revealed that there were differences in the gene expression of dermal fibroblasts from carriers of the L68Q-CST3 mutation compared to that of controls. For example, the carrier cells had elevated expression of select ECM protein genes.
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. One plausible explanation for this reduction is a gradual change in some environmental factors that began around 1825 and reached saturation around 1900. 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. A ketogenic diet is defined as a diet that induces the production of ketone bodies as alternative energy sources. One such ketone body is ß-hyroxybutyrate, which has recently been shown to be a histone deacetylases inhibitor (HDACi). This raised the question whether epigenetic gene control, specifically histon acetylation, could be a factor in HCCAA pathogenesis.
In this study eight HDACi of various specificity were used to evaluate if it was possible to “correct” the expression of a selected group of genes that were differently expressed in L68Q-CST3 dermal fibroblasts (compared to controls) in previous experiments, with special emphasis on genes that were highly up- or down regulated and/or where there was no overlap in expression pattern between carrier and control cells. Examples of this are ACAN and HOXD10. ACAN encodes for the proteoglycan aggrecan and it was the most up-regulated gene in untreated carrier fibroblasts. HOXD10 encodes for a transcriptional factor and it was the most downregulated gene in untreated carrier fibroblasts. Furthermore, two specific micro-RNAs, miR-145 and miR-10b, have been shown to influence expression levels of ACAN and HOXD10, respectively. We evaluated if the difference in the expression pattern of these genes could be a result of modified expression of miR-145 and miR-10b in the carrier fibroblasts.
|Ritgerð Gyða Ósk.pdf