Facioscapulohumeral muscular dystrophy (FSHD) is a progressive skeletal muscle disorder that mainly affects the muscles of the face, shoulders and upper arms. Skeletal muscle wasting in FSHD is... Show moreFacioscapulohumeral muscular dystrophy (FSHD) is a progressive skeletal muscle disorder that mainly affects the muscles of the face, shoulders and upper arms. Skeletal muscle wasting in FSHD is caused by the failure to epigenetically repress the transcription factor DUX4 that is typically expressed during early development. DUX4 expression in skeletal muscle induces several myotoxic cascades that ultimately lead to the death of skeletal muscles cells. At the moment there is no molecular therapy that can delay or stop disease progression. The work described in this thesis mainly aims to gain more insight in the different FSHD mouse models and the in vivo testing of new therapies in FSHD mice. We describe the generation of one new mouse model and the characterization of two other FSHD mouse models. In addition, we tested a RNA therapy that blocks the DUX4 transcript in vivo. We show that this therapy could reduce DUX4 and DUX4 target genes in FSHD mice. In addition, the therapy alleviated the severity of skeletal muscle pathology. With the data described in this thesis we hope to accelerate the development and testing of new therapies for a disease that cannot be treated until this day. Show less
Green, C.; Sydow, A.; Vogel, S.; Anglada-Huguet, M.; Wiedermann, D.; Mandelkow, E.; ... ; Hoehn, M. 2019
The main cause of cardiovascular disease (CVD) is atherosclerosis. Several genes that affect atherosclerosis development have been identified by the use of genetically modified mice (i.e.... Show moreThe main cause of cardiovascular disease (CVD) is atherosclerosis. Several genes that affect atherosclerosis development have been identified by the use of genetically modified mice (i.e. transgenic and knock-out mouse models). Many of these genes exert their role in atherosclerosis development as a result of effects on lipoprotein metabolism and inflammation. Transgenic mouse models have also been proven to be suitable for evaluating the mechanisms underlying the anti-atherosclerotic action of experimental drugs aimed to reduce atherogenic lipoprotein levels. However, thus far no suitable animal model was present to evaluate the mechanism of action of anti-atherosclerotic effect of HDL-raising therapeutic strategies. In this thesis, we further explored the role of apolipoprotein CI (apoCI) and cholesteryl ester transfer protein (CETP) in lipoprotein metabolism, inflammation, and atherosclerosis. Furthermore, we developed a mouse model that will be suitable for testing potential high-density-lipoprotein (HDL) raising therapies as a novel strategy to treat CVD. Show less
