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Characterizing intracellular lipid signaling in dilated cardiomyopathy using human iPSC-derived cardiac cells

dc.contributor.advisorEbert, Antje PD Dr.
dc.contributor.authorIgnatyeva, Nadezda
dc.date.accessioned2023-04-18T14:02:04Z
dc.date.issued2023-04-18
dc.identifier.urihttp://resolver.sub.uni-goettingen.de/purl?ediss-11858/14628
dc.identifier.urihttp://dx.doi.org/10.53846/goediss-9835
dc.format.extentXXX Seitende
dc.language.isoengde
dc.subject.ddc570de
dc.titleCharacterizing intracellular lipid signaling in dilated cardiomyopathy using human iPSC-derived cardiac cellsde
dc.typecumulativeThesisde
dc.contributor.refereeEbert, Antje PD Dr.
dc.date.examination2023-03-29de
dc.description.abstractengSarcomere protein misalignment is a primary consequence of inherited mutations causing dilated cardiomyopathy (DCM) and results in severe molecular patho-phenotypes in cardiomyocytes from patients. In this study, human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) carrying mutations in troponin T (TnT-R173W, TnT-R141W) and tropomyosin in combination with CRISPR/Cas9 genome editing were used as a model to investigate novel disease mechanisms in DCM. We revealed attenuated interactions between the sarcomere and other organelles in DCM iPSC-CMs and resulting downstream patho-phenotypes, such as defective lipid signaling. Using super-resolution stimulated emission depletion (STED) imaging, we described molecular disorganization and defective endosome distribution in patient-derived or CRISPR/Cas9 mutation-introduced iPSC-CMs. Moreover, we applied a quantitative assessment to recapitulate vesicle distribution in DCM iPSC-CMs as well as WT controls. Treatment of DCM iPSC-CMs with a small molecule chemical, a RhoA activating peptide, or CRISPR/Cas9-based genomic mutation-correction, rescued these molecular dysfunctions. Vice versa, applying a lipid signaling modifier to WT iPSC-CMs introduced the molecular patho-phenotype of abnormal protein-protein interactions and signaling observed previously in DCM iPSC-CMs into the WT controls. We corroborated our findings using assessment of left ventricular tissues from patients with end-stage heart failure due to DCM or other conditions compared to tissues from healthy donors. Tissues of failing hearts were found to display the molecular signaling patho-phenotype including altered protein expression. This suggested defective organization of organellar microdomains and subsequent pathological lipid signaling as well as dysregulated metabolite homeostasis. This molecular disease mechanism may potentially be present also in systolic heart failure due to other reasons than DCM, although further studies are required to clarify this point. Altogether, we revealed a novel patho-mechanistic crosstalk of dysregulated protein-protein interactions and defective lipid signaling in human models of DCM. Our research may contribute to potential translational and therapeutic directions in cardiac disease.de
dc.contributor.coRefereeRizzoli, Silvio O. Prof. Dr.
dc.subject.engsarcomere protein mutationsde
dc.subject.engiPSC-CMsde
dc.subject.engdilated cardiomyopathy DCMde
dc.subject.engheart failurede
dc.subject.engdruggable targetsde
dc.subject.engendoplasmic reticulumde
dc.subject.engendosome distributionde
dc.identifier.urnurn:nbn:de:gbv:7-ediss-14628-5
dc.date.embargoed2025-03-28
dc.affiliation.instituteBiologische Fakultät für Biologie und Psychologiede
dc.subject.gokfullBiologie (PPN619462639)de
dc.description.embargoed2025-03-28de
dc.identifier.ppn184324098X
dc.notes.confirmationsentConfirmation sent 2023-04-18T14:15:01de


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