University of Twente Student Theses


Hypertrophic cardiomyopathy : the changes in the non sarcomeric cytoskeleton linked to the nucleus

Bloem, J.S. (2023) Hypertrophic cardiomyopathy : the changes in the non sarcomeric cytoskeleton linked to the nucleus.

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Abstract:Hypertrophic cardiomyopathy (HCM) is an inheritable cardiovascular disease which is characterized by thickening of the septum and left ventricular wall, leading to impaired relaxation and obstruction of the left ventricular outflow tract. Recent research shows that alterations in the non-sarcomeric cytoskeleton, including microtubules and intermediate filaments, play a role in the pathogenesis of HCM by their significant increase in HCM and thereby contributing to the observed nuclear deformations. This study aimed to investigate the changes in the non-sarcomeric cytoskeleton in HCM cardiomyocytes and how they are related to the deformations of the nucleus. Three main objectives were included: First, separating the polymerized and free form of tubulin from each other to examine polymerized tubulin protein levels and correlate them with nuclear parameters . Secondly, examining nuclear proteins lamin A/C and γH2AX levels and their correlation with nuclear parameters and non-sarcomeric component levels. Third, assessing the effect of different compounds affecting microtubules on the contractility of cells using a mouse model. Although the results of the first objective were inconclusive due to the issue that the polymerized and free fraction of tubulin could not properly be separated, the study found an increase in nuclear proteins lamin A/C and γH2AX levels in HCM compared to non-failing (NF) donors. Furthermore, the correlations suggest that lamin A/C acts as a protective mechanism for chromatin against mechanical stress applied on the nucleus to prevent DNA damage. The mouse model suggests that stable microtubules support cardiomyocyte contractility, and that detyrosination contributes to impaired contraction in cardiomyocytes, but further testing is needed to draw more reliable conclusions. Together, the study aims to shed more light on the molecular mechanisms underlying HCM, specifically focusing on the interplay between the cytoskeleton and the nucleus. Overall, the goal was to contribute to the identification of potential therapeutic targets for regenerative treatments, and in the end improve patient outcomes.
Item Type:Essay (Master)
Amsterdam UMC, Amsterdam, Netherlands
Faculty:TNW: Science and Technology
Subject:35 chemistry, 42 biology, 44 medicine, 50 technical science in general
Programme:Biomedical Engineering MSc (66226)
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