MICA: Interfering with pathological signalling in dilated cardiomyopathy
Lead Research Organisation:
King's College London
Department Name: Cardiovascular
Abstract
We have shown previously that the general architecture of a heart cell is changed in dilated cardiomyopathy, a disease that leads to ballooning of the heart and to less blood pumping ability. More recently we demonstrated that this directly also changes the localization of signaling factors that are important in heart disease by keeping them in a complex close to the plasma membrane of the cell. Breaking up this complex in mouse models of dilated cardiomyopathy by genetic means prevented the disease and we now want to find drugs that can break up this complex, too. Aim of this project is 1) to study the assembly of this complex in a cell culture model for stressed heart cells, 2) identify exactly which parts of the complex interact at the amino acid level and 3) screen for drugs that can prevent the formation of this complex. If we can find a drug that works, we can in the future test whether it also prevents dilated cardiomyopathy in mouse models. This may be the first step on a new way to treat heart disease.
Technical Summary
We have recently demonstrated the existence of a multiprotein complex at the intercalated disc, the specialized type of cell-cell contact in the heart, that is crucial for chronical pathological signaling in dilated cardiomyopathy (DCM). It consists of the signaling molecules PKCalpha and PLCbeta1 together with the adaptor protein CARP1. Breaking up this complex in a mouse model of DCM, the MLP knockout mouse, by removing CARP1 via genetic means prevents the development of the DCM phenotype at the histological, functional and molecular level. We propose that interference with the formation of this complex could slow down the kind of sustained pathological signaling that leads to heart failure. In this proposal we aim to study this complex more closely at the cellular and the molecular level and to start to screen for small compounds that could prevent the formation of this complex using high throughout screening of a compound library from Astra Zeneca and a fluorescence based cellular assay system. The expected results will tell us whether this strategy would indeed be promising in attenuating the kind of pathological signaling that leads to heart failure.
Planned Impact
This project may in the long run lead to a new drug to combat heart disease. We have identified a detrimental signalling complex that is active in dilated cardiomyopathy and want to identify drugs that prevent the formation of this complex. The research that we will carry out in this project will study the dynamics and molecular basis of the formation of this complex and will start a pilot screen of a compound library of a pharmaceutical company with the aim of identifying suitable compounds by a fluorescence based screen that interfere with the formation of the signalling complex. Therefore apart from the gain of knowledge from understanding better which molecular processes are involved in pathological signalling in the heart, the work will hopefully lead to the identification of a compound that can in the future be further scrutinised for its efficacy in animal models for dilated cardiomyopathy.
Organisations
People |
ORCID iD |
Elisabeth Ehler (Principal Investigator) |
Publications
Appelt D
(2022)
Polarized illumination coded structured illumination microscopy (picoSIM): experimental results.
in Philosophical transactions. Series A, Mathematical, physical, and engineering sciences
Brayson D
(2019)
Prelamin A mediates myocardial inflammation in dilated and HIV-associated cardiomyopathies
in JCI Insight
Broadway-Stringer S
(2023)
Insights into the Role of a Cardiomyopathy-Causing Genetic Variant in ACTN2.
in Cells
Chandler J
(2023)
In situ FRET-based localization of the N terminus of myosin binding protein-C in heart muscle cells.
in Proceedings of the National Academy of Sciences of the United States of America
Crestani T
(2020)
Electrical stimulation applied during differentiation drives the hiPSC-CMs towards a mature cardiac conduction-like cells.
in Biochemical and biophysical research communications
Dark N
(2023)
Generation of left ventricle-like cardiomyocytes with improved structural, functional, and metabolic maturity from human pluripotent stem cells.
in Cell reports methods
Diering S
(2020)
Receptor-independent modulation of cAMP-dependent protein kinase and protein phosphatase signaling in cardiac myocytes by oxidizing agents.
in The Journal of biological chemistry
Ehler E
(2021)
Biophysical Reviews "Meet the Editor Series"-Elisabeth Ehler.
in Biophysical reviews
Jiang H
(2021)
Functional analysis of a gene-edited mouse model to gain insights into the disease mechanisms of a titin missense variant.
in Basic research in cardiology
Lange S
(2020)
The M-band: The underestimated part of the sarcomere.
in Biochimica et biophysica acta. Molecular cell research
Description | Participation in STARS programme |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | Annual STARS programme at King's (Science Training for Aspiring Research Scientists): 15 yr12 students from schools across London with a poor record of sending their kids to HEI's are brought to King's for a week of science training and fun. I held a workshop with them, where they performed an experiment on heart cells and then took images on a fluorescent microscope - most of them were keen on taking "their" image home with them! |
Year(s) Of Engagement Activity | 2018,2019 |