AG Kowalski
Unequal allelic expression (from cell to cell) as a pathomechanism for Hypertrophic Cardiomyopathy
Contact:
Dr. rer. nat. Kathrin Kowalski
Adress: MHH, Institut für Molekular- und Zellphysiologie
Carl-Neuberg-Straße 1, 30625 Hannover, Germany
Campus, Building J03, Block 01, Floor 03, Room 1320
Telephone (+49) 511 532 2759
Fax (+49) 511 532 4296
E-Mail Dr. rer. nat. Kathrin Kowalski
Research focus
We examine the unequal expression of wildtype and mutant alleles in heterozygous patients with hypertrophic cardiomyopathy (HMC) as a potenial pathomechanism.
In previous work in our department, we could show that force generation differs severely between cardiomyocytes from the very same patient at the same calcium concentration. We hypothesized that this functional heterogeneity between neighboring cardiomyocytes may disrupt the myocardial network. This may lead to hallmarks of HCM such as cardiomyocyte and myofibrillar disarray, hypertrophy and fibrosis („contractile imbalance hypothesis”).
The special focus of our research group are the molecular mechanism underlying the contractile imbalance. We analyse the allele specific mRNA expression in single cardiomyocytes from cryosections of HCM patients and heart-healthy controls and in human induced pluripotent stem cells. We could show that individual cardiomyocytes express highly divergent fraction of mutant per wildtype mRNA. In addition, we visualize active transcription sites in individual nuclei to examine whether burst-like transcription, a stochastic and independent on and off switch of the alleles, may cause the allelic imbalance from cell to cell.
Group members:
Mariane Fráguas-Eggenschwieler
technic stuff
Karina Schlosser
qualification work running / current:
Dr. med. (StrucMed-Programm)
Felix Wilczak (Prof. Dr. J. Montag Medical School Berlin)
Philemon Libertus (Prof. Dr. J. Montag Medical School Berlin)
Benita Haß
qualification work ended
Bachelor theses:
Luisa Schwarze (2023)
Publication
2023
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Nonsense mediated decay factor UPF3B is associated with cMyBP-C haploinsufficiency in hypertrophic cardiomyopathy patients, Valentin Burkart, Kathrin Kowalski, Alina Disch, Denise Hilfiker-Kleiner , Sean Lal , Cristobal dos Remedios, Andreas Perrot, Andre Zeug, Evgeni Ponimaskin, Maike Kosanke, Oliver Dittrich-Breiholz, Theresia Kraft, Judith Montag, Journal of Molecular and Cellular Cardiology Volume 185 (2023) pages: 26–37, https://doi.org/10.1016/j.yjmcc.2023.09.008, Online ahead of print
2022
- Transcriptional bursts and heterogeneity among cardiomyocytes in hypertrophic cardiomyopathy, Valentin Burkart, Kathrin Kowalski, David Aldag-Niebling, Julia Beck, Dirk Alexander Frick, Tim Holler, Ante Radocaj, Birgit Piep, Andre Zeug, Denise Hilfiker-Kleiner, Cristobal G. dos Remedios, Jolanda van der Velden, Judith Montag and Theresia Kraft, Front. Cardiovasc. Med., August 2022, Sec. Cardiovascular Biologics and Regenerative Medicin, doi: 10.3389/fcvm.2022.987889
2020
- Advanced Single-Cell Mapping Reveals that in hESC Cardiomyocytes Contraction Kinetics and Action Potential Are Independent of Myosin Isoform, Natalie Weber, Kathrin Kowalski, Tim Holler, Ante Radocaj, Martin Fischer, Stefan Thiemann, Jeanne de la Roche, Kristin Schwanke, Birgit Piep, Neele Peschel, Uwe Krumm, Alexander Lingk, Meike Wendland, Stephan Greten, Jan Dieter Schmitto, Issam Ismail, Gregor Warnecke, Urs Zywietz, Boris Chichkov, Joachim Meißner, Axel Haverich, Ulrich Martin, Bernhard Brenner, Robert Zweigerdt, Theresia Kraft, stem cell report, Published:April 16, 2020, DOI: https://doi.org/10.1016/j.stemcr.2020.03.015, Journal free
2018
- Burst-Like Transcription of Mutant and Wildtype MYH7 -Alleles as Possible Origin of Cell-to-Cell Contractile Imbalance in Hypertrophic Cardiomyopathy, Montag, J., Kowalski, K., Makul, M., Ernstberger, P., Radocaj, A., Beck, J., Becker, E., Tripathi, S., Keyser, B., Mühlfeld, C., Wissel, K., Pich, A., van der Velden, J., dos Remedios, C. G., Perrot, A., Francino, A., Navarro-López, F., Brenner, B., & Kraft, T. (2018). Front. Physiol. 9, 1–15. doi:10.3389/fphys.2018.00359
Scientific articles in peer-reviewed journals
2023
-
Nonsense mediated decay factor UPF3B is associated with cMyBP-C haploinsufficiency in hypertrophic cardiomyopathy patients, Valentin Burkart, Kathrin Kowalski, Alina Disch, Denise Hilfiker-Kleiner , Sean Lal , Cristobal dos Remedios, Andreas Perrot, Andre Zeug, Evgeni Ponimaskin, Maike Kosanke, Oliver Dittrich-Breiholz, Theresia Kraft, Judith Montag, Journal of Molecular and Cellular Cardiology Volume 185 (2023) pages: 26–37, https://doi.org/10.1016/j.yjmcc.2023.09.008, Online ahead of print
2022
- Transcriptional bursts and heterogeneity among cardiomyocytes in hypertrophic cardiomyopathy, Valentin Burkart, Kathrin Kowalski, David Aldag-Niebling, Julia Beck, Dirk Alexander Frick, Tim Holler, Ante Radocaj, Birgit Piep, Andre Zeug, Denise Hilfiker-Kleiner, Cristobal G. dos Remedios, Jolanda van der Velden, Judith Montag and Theresia Kraft, Front. Cardiovasc. Med., August 2022, Sec. Cardiovascular Biologics and Regenerative Medicin, doi: 10.3389/fcvm.2022.987889
2020
- Advanced Single-Cell Mapping Reveals that in hESC Cardiomyocytes Contraction Kinetics and Action Potential Are Independent of Myosin Isoform, Natalie Weber, Kathrin Kowalski, Tim Holler, Ante Radocaj, Martin Fischer, Stefan Thiemann, Jeanne de la Roche, Kristin Schwanke, Birgit Piep, Neele Peschel, Uwe Krumm, Alexander Lingk, Meike Wendland, Stephan Greten, Jan Dieter Schmitto, Issam Ismail, Gregor Warnecke, Urs Zywietz, Boris Chichkov, Joachim Meißner, Axel Haverich, Ulrich Martin, Bernhard Brenner, Robert Zweigerdt, Theresia Kraft, stem cell report, Published:April 16, 2020, DOI: https://doi.org/10.1016/j.stemcr.2020.03.015, Journal free
2018
- Burst-Like Transcription of Mutant and Wildtype MYH7 -Alleles as Possible Origin of Cell-to-Cell Contractile Imbalance in Hypertrophic Cardiomyopathy, Montag, J., Kowalski, K., Makul, M., Ernstberger, P., Radocaj, A., Beck, J., Becker, E., Tripathi, S., Keyser, B., Mühlfeld, C., Wissel, K., Pich, A., van der Velden, J., dos Remedios, C. G., Perrot, A., Francino, A., Navarro-López, F., Brenner, B., & Kraft, T. (2018). Front. Physiol. 9, 1–15. doi:10.3389/fphys.2018.00359
Publication Abstracts for Lectures
Burkart V., Kowalski K., Holler T., Hilfiker-Kleiner D., Lal S., dos Remedios C. G., Perrot A., Ho C., Dittrich-Breiholz O., Kraft T., Montag J., MYBPC3-haploinsufficiency in hypertrophic cardiomyopathy patients is associated with nonsense mediated decay factor UBF3B. 2022, J Muscle Res Cell Motil
Montag J., Weber N., Kowalski K., Mayer A.-K., Iorga B., Brunkhorst A., Zweigerdt R., Kraft T., Human pluripotent stem cell-derived cardiomyocytes mimic intercellular heterogeneity as pathomechanism in Hypertrophic Cardiomyopathy, 2022, Acta Physiologica, Vol.236, Issue S725
Burkart V., Kowalski K., Holler T., Hilfiker-Kleiner D., Lal S., dos Remedios C. G., Perrot A., Seidman C. E., Kosanke M., Kraft T., Montag J., Alterations of sarcomeric stoichiometry by nonsense mediated decay of MYBPC3-mRNA in hypertrophic cardiomyopathy patients with truncation mutations. 2022, Biophysical Journal, Vol.121, Issue 3, Suppl., 1, 435a
Kowalski K., Mayer A.-K., Piep B., Zweigerdt R., Schwanke K., Kraft T., Montag J. Burst-like transcription of MYH7 in Hypertrophic Cardiomyopathy patients is mimicked in patient-derived hPSC-CMs; Acta Biochimica Polonica, Vol. 68 No. S1, 57; 2021
Burkart V., Kowalski K., Beck J., Aldag-Niebling D., Radocaj A., Keyser B., van der Velden J., dos Remedios C., Hilfiker-Kleiner D., Kraft T., Montag J. Burst-like transcription of sarcomeric genes in hypertrophic cardiomyopathy. 2021, Biophysical Society Journal, Vol. 120, Issue 3, Suppl. 1, 103a
Weber N.*, Kowalski K.*, Holler T., Radocaj A., Fischer M., de la Roche J., Thiemann S., Schwanke K., Lingk A., Krumm U., Piep B., Martin U., Zweigerdt R., Brenner B., Kraft T., In human embryonic stem cell-derived cardiomyocytes twitsch kinetics, action potential parameters and MyH-mRNA fractions are independent of the expressed myosin heavy chain isoform, 2019, Biophysical Society Journal, Vol.116, Issue 3, Suppl. 1, 118A * gleichwertiger Beitrag der Autoren
Kowalski K., Radocaj A., Francino A., Navarro-López F., dos Remedios C. G., Kraft T., Brenner B. Detection of transcription sites in FHC patients indicating a burst-like transcription concept for MYH7. 2017, Acta Physiol. 219 (S711):47
Radocaj A., Kowalski K., Montag J., Kraft T., Brenner B. Independent Stochastic Burst-like Transcription of Mutant and Wildtype Alleles as Mechanism for Cell-to-Cell Functional Imbalance in Hypertrophic Cardiomyopathy. 2017, Biophysical Journal, Vol. 112, Issue 3, p164a
Kraft T., Kowalski K., Montag J., Radocaj A., Makul M., Ernstberger P., Perrot A., Francino A., Navarro-López F., Brenner B. Hypertrophic Cardiomyopathy: Random burst-like transcription of wildtype and mutated allele as trigger for phenotype development. 2016, Circulation, Vol. 134, Issue suppl_1
Publication Abstracts for poster
Kowalski K., Riesselmann J.N., Weber N., Piep B., Franke A., Martin U., Zweigerdt R., Kraft T., Presence of T3 reduces active transcription of MYBPC3 and TNNI3 in cardiomyocytes; 2022, J Muscle Res Cell Motil
Burkart V., Kowalski K., Beck J., Aldag-Niebling D., Holler T., Radocaj A., Keyser B., van der Velden J., Lal S., dos Remedios C., Hilfiker-Kleiner D., Kraft T., Montag J. Burst-like transcription of sarcomeric genes is associated with cell-to-cell allelic and functional heterogeneity in Hypertrophic Cardiomyopathy; Acta Biochimica Polonica, Vol 68 No. S1, 48; 2021
Kowalski K., Riesselmann J.N., Weber N., Piep B., Franke A., Martin U., Zweigerdt R., Kraft T., T3 reduces transcriptional activty of MYBPC3 and TNNI3. 2021, Acta Physiol.
Kowalski K., Riesselmann J.N., Weber N., Piep B., Franke A., Martin U., Zweigerdt R., Kraft T., Influence of T3 on active transcription of MYBPC3 and TNNI3. 2021, Biophysical Society Journal, Vol. 120, Issue 3, Suppl. 1, 136a
Burkart V., Beck J., Kowalski K., van der Velden J., dos Remedios C. G., Montag J., Kraft T., Unequal allelic expression of mutated cardiac troponin I from cell-to-cell may induce contractile imbalance in Hypertrophic Cardiomyopathy. 2020, Biophysical Society Journal, Vol.118, Issue 3, Suppl.1, 424a
Kowalski K., Weber N., Holler T., Radocaj A., Fischer M., de la Roche J., Thiemann S., Schwanke K., Piep K., Piep B., Lingk A., Krumm U., Martin U., Zweigerdt R., Brenner B., Kraft T., Twitch kinetics and action potential parameters are independent of expressed myosin heavy chain isoform in human embryonic stem cell-derived cardiomyocytes. 2019, Acta Physiol. 227 (S719):146
Burkart V., Beck J., Kowalski K., van der Velden J., dos Remedios C. G., Montag J., Kraft T., Allelic imbalance of TNNI3 trough burst-like transcription may lead to contractile imbalance in hypertrophic cardiomyopathy patients. 2019, J Muscle Res Cell Motil 40
Makul M., Radocaj A., Ernstberger P., Montag J., Kowalski K., Keyser B., Perrot A., dos Remedios C. G., Brenner B., Kraft T. Myosin and cMyBP-C-mutations in Hypertrophic cardiomyopathy: Variable effects on calcium sensitivity and contractile imbalance from cell-to-cell, 2019, Biophysical Society Journal, Vol.116, Issue 3, Suppl. 1, 262A
Weber N.*, Kowalski K.*, Holler T., Radocaj A., Schwanke K., Lingk A., Krumm U., Wendland M., Zywietz U., Chickov B., Ulrich M., Zweigerdt R., Brenner B., Kraft T. Human embryonic stem-cell derived cardiomyocytes: Single-Cell Mapping to relate twitch kinetics to myosin heavy chain protein and mRNA-expression, 2018, Biophysical Journal, Vol.114, Issue 3, p.549a * gleichwertiger Beitrag der Autoren
Kowalski K., Radocaj A., Francino A., Navarro-López F., dos Remedios C. G., Kraft T., Brenner B. Visualization of active transcription sites in human cardiomyocytes supports the concept of burst-like transcription of MYH7. 2017, Biophysical Journal Vol. 112, Issue 3, Supplement 1, 210a
Kowalski K., Radocaj A., Francino A., Navarro-López F., dos Remedios C. G., Kraft T., Brenner B. Analysis of active transcription sites in single human cardiomyocytes reveals burst-like transcription of MYH7. 2017, J Muscle Res Cell Motil 38:360
Radocaj A., Kowalski K., Montag J., Kraft T., Brenner B. Model of independent stochastic burst-like transcription can explain observed functional and transcriptional variability among cardiomyocytes from Hypertrophic Cardiomyopathy patients. 2017, J Muscle Res Cell Motil 38:362
Radocaj A., Kowalski K., Montag J., Kraft T., Brenner B. Independent, stochastic, burst-like transcription of mutant and wildtype MYH7-alleles. A mechanism for functional and transcriptional variability among HCM (hypertrophic cardiomyopathy) cardiomyocytes. 2017, Acta Physiol. 219(S711):132
Weber N., Kowalski K., Holler T., Lingk A., Radocaj A., Krumm U., Wendland M., Zywietz U., Chichkov B., Schwanke K., Martin U., Zweigerdt R., Brenner B., Kraft T. Singe cell mapping used to assign mRNA and protein expression of cardiac myosin heavy chain to twitch kinetics of the same human embryonic stem cell-derived cardiomyocyte. 2017, J Muscle Res Cell Motil 38:344
- Laser microdissection
- (Single cell-) Reverse Transcriptase PCR (RT-PCR)
- single molecule RNA-fluorescence in situ hybridisation (smRNA-FISH)
- Kontraktions- und Ca2+-Transientenmeasurement with MyoCam (IonOptix)
- Genome editing, knock-in of a point mutation (CRISPR/Cas9)
- cell culture (hiPSC)
- Practical courses for medical students, dentists and biologists
- Seminars for medical students
- Bachelor theses in Biology and Biochemistry
- PhD theses in Biology and Medicine
- Supervision of qualification work