| dc.contributor.advisor | Hasenfuß, Gerd Prof. Dr. | |
| dc.contributor.author | Hindmarsh, Vanessa | |
| dc.date.accessioned | 2022-01-21T11:41:01Z | |
| dc.date.available | 2022-01-28T00:50:09Z | |
| dc.date.issued | 2022-01-21 | |
| dc.identifier.uri | http://hdl.handle.net/21.11130/00-1735-0000-0008-59FB-A | |
| dc.identifier.uri | http://dx.doi.org/10.53846/goediss-9056 | |
| dc.identifier.uri | http://dx.doi.org/10.53846/goediss-9056 | |
| dc.language.iso | eng | de |
| dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/4.0/ | |
| dc.subject.ddc | 610 | |
| dc.title | The role of CRISPLD1 in the transition to heart failure | de |
| dc.type | doctoralThesis | de |
| dc.contributor.referee | Wollnik, Bernd Prof. Dr. | |
| dc.date.examination | 2021-12-14 | |
| dc.description.abstracteng | Heart failure is a leading cause of death worldwide. It is defined as a condition in which the heart is unable to pump a sufficient amount of blood through the body to satisfy its oxygen need and can be caused by various cardiac diseases. Although several mechanisms are already identified to play a role in the transition to HF, there is still a lack of knowledge about the precise mechanisms. To gain better insights into these mechanisms, previous studies in the group performed RNA-sequencing of human myocardium samples from patients suffering from aortic stenosis with compensated hypertrophy or heart failure. The obtained dataset was compared to data from analogous progression stages in the transverse aortic constriction mouse model to identify novel target genes in the disease. Among these genes, CRISPLD1 showed conserved expression levels and was upregulated during the transition to heart failure in human and mouse. Protein structure analysis identified a V5/Tpx-1 related conserved site which is known to be evolutionary related to the toxin helothermine, that regulates calcium homeostasis. To elucidate the function of CRISPLD1 in the heart, induced pluripotent stem cell derived cardiomyocytes (iPSC-CMs) and two knockout mouse models were analyzed. CRISPLD1-deficient iPSC-CMs were generated via CRISPR/Cas9 and showed dysregulation of calcium handling. Transcriptome analysis of these cells revealed a downregulation of prohypertrophic, proapoptotic and calcium-regulating pathways, suggesting CRISPLD1 loss-of-function as being beneficial in response to cardiomyocyte stress. However, analysis of Crispld1-deficient knockout mouse lines showed contrary results. While the ubiquitous Crispld1 knockout mouse line did not show any phenotype, the heart-specific Crispld1 knockout mouse line displayed a severe dilated cardiac phenotype with increased mortality. Analysis of hypertrophic markers, measurement of cardiomyocyte hypertrophy or fibrosis did not indicate any alterations. Even more, calcium cycling evaluations of isolated mouse cardiomyocytes could not confirm the findings of iPSC-CMs and again no alterations comparing the mouse lines were observed. Although, the severe cardiac phenotype of heart-specific Crispld1 knockout mice could not be explained, results obtained in cell culture were promising and identified CRISPLD1 as playing a role in calcium cycling in CMs. In conclusion, the findings from this thesis give first insights into the potential role of CRISPLD1 as a calcium regulator in the heart in a human and murine model system. However, future research is necessary to identify its specific role and explain the severe mouse phenotype. | de |
| dc.contributor.coReferee | Katschinski, Dörthe Prof. Dr. | |
| dc.contributor.thirdReferee | Streckfuß-Bömeke, Katrin Dr. | |
| dc.contributor.thirdReferee | Zelarayán, Laura C. Dr. | |
| dc.contributor.thirdReferee | Dressel, Ralf Prof. Dr. | |
| dc.contributor.thirdReferee | Kensah, George Dr. | |
| dc.subject.eng | Heart failure | de |
| dc.subject.eng | iPS | de |
| dc.subject.eng | Cardiovascular diseases | de |
| dc.subject.eng | CRISPLD1 | de |
| dc.subject.eng | Stem cells | de |
| dc.identifier.urn | urn:nbn:de:gbv:7-21.11130/00-1735-0000-0008-59FB-A-2 | |
| dc.affiliation.institute | Medizinische Fakultät | |
| dc.subject.gokfull | Molekulare Medizin | de |
| dc.description.embargoed | 2022-01-28 | |
| dc.identifier.ppn | 1786946246 | |
| dc.creator.birthname | Kernke | de |