Experimental Studies of Disease-Associated AS Events

The overall goal of SP4 is to validate and to characterize AS events identified in SP1 with a therapeutic perspective for the treatment of DCM and HN patients. To this end, we will use human tissue, animal models (mouse and zebrafish) and cell cultures. Additionally, we will generate Omics data from the animal and cell culture models for multiple time points. This will allow us to investigate the disease development and progression and to improve causality assessment of AS events. AS is evaluated in cardiac tissue and whole blood of transgenic heart failure animals using RNA-seq and proteome analyses. For association of the results with the disease stage, the animals will further be characterised by echocardiography, immunohistochemical analyses and ELISA. Furthermore, we will compare this to results gained from human (SP 1-3). In vivo targeting of selected splicing sites will be performed as a proof-of concept study using two selected antisense oligonucleotides. Concerning HN, we will stain archived tissue slices from kidney biopsies of HN patients to examine whether AS events identified in the blood of HN patients (SP1 and 2) also occur in the kidney of HN patients. We will prepare samples for the identification of AS events by Omics analysis in two model systems relevant for HN: 1) glomerular injury by podocyte depletion in zebrafish larvae, and 2) stretching cultured podocytes to simulate glomerular hypertension. Shared AS events between HN patients and our model systems will be mechanistically studied in the two model systems to clarify whether HN could be treated by manipulation of AS events, e.g. by antisense oligonucleotides.

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