the projects -
Mechanisms and signaling pathways important for the development of dilated cardiomyopathy (DCM)
Dilated cardiomyopathy (DCM) can at the moment only be treated by heart transplantation. The scarcity of donor hearts makes it pertinent to explore disease mechanisms and identify possible strategies to alleviate this disease.
We are currently investigating a signaling pathway that leads to the maladaptation of the heart and results in the development of dilated cardiomyopathy.
Functions of the ankyrin repeat domain protein family
Our studies revealed crucial functions of the ankyrin repeat domain protein family, and particularly its members CARP1/Ankrd1 and CARP2/Ankrd2, for the development of dilated cardiomyopathy in a mouse model of this disease. In collaboration with Dr. Elisabeth Ehler from King's College London, Dr. Katja Gehmlich from Oxford University and Dr. Cristobal dos Remedios from the University of Sydney we outlined that the signaling pathway involving Ankrd1 and Ankrd2, as well as protein kinase C (alpha) and MLP might be responsible for DCM development in a subset of human patients.
Our findings were recently published in the journal Nature Communications and can be found here:
MLP and CARP are linked to chronic PKCα signalling in dilated cardiomyopathy. Nat Commun. 2016 Jun 29.
Parts of this project were done in collaboration with ACEA, a San Diego based biotech company. We used their xCELLigence cardio-system to characterize contractile parameters of neonatal mouse cardiomyocyte cultures derived from the MLP knockout mouse model for dilated cardiomyopathy in a high throughput, high replicate fashion. More information can be found here.
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Future Directions
Main objectives are to investigate and understand:
- novel pathway components of the signaling pathway involving Ankrd proteins
- pathological changes to cardiac signaling pathways that are responsible for the development of DCM in human patients and mouse models for this disease,
- how interventions in specific signaling events can suppress the disease development and progression.
Related manuscripts
- PKC and PKN in heart disease. J Mol Cell Cardiol. 2019 Feb 8. doi.org/10.1016/j.yjmcc.2019.01.029 PMID: 30742812
- Mutant Muscle LIM Protein C58G causes cardiomyopathy through protein depletion. J Mol Cell Cardiol. 2018 Jul 23. doi: 10.1016/j.yjmcc.2018.07.248. PMID: 30048712
- MLP and CARP are linked to chronic PKCα signalling in dilated cardiomyopathy. Nat Commun. 2016 Jun 29. doi: 10.1038/ncomms12120. PMID: 27353086
- Probing Muscle Ankyrin-Repeat Protein (MARP) Structure and Function. Anat Rec. 2014 Aug;14. DOI: 10.1002/ar.22968. read at the publisher >
Collaborators on this project
- Dr. Elisabeth Ehler, King's College London, UK
- Dr. Katja Gehmlich, Oxford University, UK
- Dr. Cristobal dos Remedios, University of Sydney, Australia
- Dr. Entela Bollano and Dr. Niklas Bergh, Sahlgrenska University Hospital, Gothenburg, Sweden
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