| dc.contributor.advisor | Parlitz, Ulrich Apl. Prof. Dr. | |
| dc.contributor.author | Cosi, Filippo Giovanni | |
| dc.date.accessioned | 2020-05-28T08:24:19Z | |
| dc.date.available | 2020-05-28T08:24:19Z | |
| dc.date.issued | 2020-05-28 | |
| dc.identifier.uri | http://hdl.handle.net/21.11130/00-1735-0000-0005-13B6-8 | |
| dc.identifier.uri | http://dx.doi.org/10.53846/goediss-7998 | |
| dc.identifier.uri | http://dx.doi.org/10.53846/goediss-7998 | |
| dc.language.iso | eng | de |
| dc.relation.uri | http://creativecommons.org/licenses/by-nc-nd/4.0/ | |
| dc.subject.ddc | 571.4 | de |
| dc.title | Impact of Structure Modification on Cardiomyocyte Functionality | de |
| dc.type | doctoralThesis | de |
| dc.contributor.referee | Parlitz, Ulrich Apl. Prof. Dr. | |
| dc.date.examination | 2020-02-27 | |
| dc.description.abstracteng | Cardiac diseases are often related to defects in subcellular components of the heart’s
main constituents, the heart muscle cells also called cardiac myocytes. These biological
cells periodically contract due to excitation-contraction coupling, i.e. an interplay of
intracellular ion dynamics and membrane potential which is centered around calcium
release units (CRUs). Especially alterations of the functions and the geometry of
CRUs may lead to distorted intracellular ion and voltage dynamics resulting in a
malfunctioning cell.
While the functions of CRUs are well studied, the knowledge about their geometry
is still incomplete. However, recently the ryanodine receptors 2 (RyRs), i.e. calcium
handling channels in CRUs, have been found to form elongated clusters rather than
being densely packed into lattice-like configurations, as was previously assumed. This
experimental observation represents a good reason to investigate the influence of the
geometrical arrangement of ionic channels on the dynamics of cardiomyocytes.
In this thesis a multiscale mathematical model is employed to quantify the impact
different RyR arrangements in CRUs have on the ion dynamics and voltage dynamics
of cardiac myocytes. The model describes the microscopic and stochastic processes of
calcium release as well as the intracellular mesoscopic ion diffusion and action potential
dynamics. Using this model we show that not only the shape of the RyR cluster, but
also the density and the arrangement of the channels are found to be relevant for the
cell dynamics. The numerical simulations proved changes in the microscopic structure
and geometry of cell components to significantly affect observed quantities like the
action potential duration or the average peak calcium concentration and thus the whole
cardiomyocyte functionality.
Moreover, since the employed mathematical model is computationally expensive, a
method for the generation and validation of a cheaper numerical model is applied. Using
this approach a meta model is generated based on the results from only a few hundred
simulation runs of the complex original model. Computationally faster regressions
based on the meta model can thus now accompany the multiscale mathematical model
improving the efficiency, with which descriptive and relevant predictions can be made. | de |
| dc.contributor.coReferee | Klumpp, Stefan Prof. Dr. | |
| dc.subject.eng | PhD Thesis | de |
| dc.subject.eng | Physics | de |
| dc.subject.eng | Multiscale Mathematical Model | de |
| dc.subject.eng | Cardiomyocytes | de |
| dc.subject.eng | Calcium Release Units | de |
| dc.subject.eng | Calcium Dynamics | de |
| dc.subject.eng | Ryanodine Receptors | de |
| dc.subject.eng | Structure Modification | de |
| dc.subject.eng | Surrogate/Meta Model | de |
| dc.identifier.urn | urn:nbn:de:gbv:7-21.11130/00-1735-0000-0005-13B6-8-4 | |
| dc.affiliation.institute | Göttinger Graduiertenschule für Neurowissenschaften, Biophysik und molekulare Biowissenschaften (GGNB) | de |
| dc.subject.gokfull | Biologie (PPN619462639) | de |
| dc.identifier.ppn | 1699000670 | |