Jonathan Samuel Achter - PhD Scholarship 2023
Project summary:
Changes to the molecular architecture of the intercalated disc in PKP2 deficiency and its consequences in ARVC
The intercalated disk (ID) plays a critical role in maintaining cardiac integrity and orchestrating the synchronized contraction of millions of cardiomyocytes. However, its molecular composition, regulation, and contribution to cardiac disease phenotypes remain only partly characterized. Using cutting-edge proximity proteomics techniques, this project aims to comprehensively map the proteins within the cardiac ID and investigate the impact of PKP2 deficiency on its molecular makeup.
Project Title
Changes to the molecular architecture of the intercalated disc in PKP2 deficiency and its consequences in ARVCChanges to the molecular architecture of the intercalated disc in PKP2 deficiency and its consequences in ARVC
Background
The ID is a specialized region located at the point of contact between cardiomyocytes, providing a physical continuum through mechanical junctions (desmosomes, adherens junctions and area composita) and intercellular channels (gap junctions). Most of the proteins linked to arrhythmogenic right ventricular cardiomyopathy (ARVC), an inherited heart disease characterized by fibrofatty infiltration of the right ventricle, are found within the ID.
Aim
This project aims to gain a deep understanding of the molecular composition of the ID and to unravel the underlying mechanisms of ARVC. By studying both normal cardiomyocytes and those deficient in plakophilin-2 (PKP2), a molecule commonly mutated in ARVC patients, a comprehensive map of ID proteins will be generated and the role of PKP2 in maintaining the ID’s molecular integrity will be defined.
Methods
I will use state-of-the-art proximity proteomics techniques in a transgenic mouse model. To ensure human relevance, findings will be intersected with proteomics data acquired from ARVC patients with genetic defects in PKP2, prior to pursuing detailed functional follow-up studies.
Jonathan Samuel Achter
- MSc
- Department of Biomedical Sciences, University of Copenhagen
Main supervisor:
Alicia Lundby, Professor, Department of Biomedical Sciences, University of Copenhagen
Co-supervisor:
Mario Delmar, Professor, Leon H. Charney Division of Cardiology, NYU-Grossman School of Medicine