HoPE Project: Heart-on-chip Proteome Evaluation for drug screening in metabolic cardiomyopathies
Federica Conte (RadboudUMC, University of Twente) and Hans Wessels (RadboudUMC) have been awarded a research grant from Stichting Stofwisselkracht to create an integrated platform for application of shotgun proteomics in 3D heart-on-chip models for patient-based drug screening in metabolic cardiomyopathies.
This project will be conducted as a collaboration between RadboudUMC (TML, Dirk Lefeber) and Twente University (Robert Passier).
Read more below.
Summary of the project/aim
Metabolic cardiomyopathies represent a large heterogeneous group of diseases of the heart associated to inborn errors of metabolism (IEM). So far, more than 1000 distinct disorders of metabolism have been described, most of which are leading cause heart failure and ultimately to death in IEM patients.
IEMs are usually caused by a genetic defect that translates into the alteration or absence of a protein that enables metabolic process within the cells. However, the mechanisms by which some of these protein alterations result in metabolic cardiomyopathies are still unknown, due to the challenges to investigate them. One of the biggest challenges of researching metabolic cardiomyopathies is the lack of human heart models that we can study and monitor in the lab. Traditionally, cardiac research is based on animals and cells grown ‘on petri dish’, but these models do not recapitulate the biology and functionality of the heart.
In the past few years, we established a platform to enable the study of the metabolism and metabolic alterations in ‘heart-on-chip’ models, called 3D engineered heart tissue. Now, thanks to the support of Stofwisselkracht and in collaboration with the University of Twente, we will expand our platform to enable the study of proteins in ‘heart-chip’ models derived from patients with PGM1-linked cardiomyopathy.
Once established and optimized, this platform will allow (1) the study of protein alterations occurring in different metabolic cardiomyopathies and (2) the identification of therapeutic strategies to address these disorders.
Summary of the research plan
The overarching goal of our HoPE project is to integrate functional in vitro heart models with advanced proteomics technology to address the need of new technological solutions to identify novel therapeutic targets and to screen heart-targeted treatments for MCMs.
To establish our HoPE technology platform within the 18-month period of this project, we envisioned three subprojects. Subproject A: in this phase we aim to generate 3D EHTs from patients affected by PGM1-linked cardiomyopathy (as first metabolic disease model). Subproject B: in this phase we will set-up the pipeline to apply shotgun proteomics to 3D-EHTs, including protocol for sample preparation, generation of peptide library and optimization of MS settings. Subproject C: in the last phase we will screen a panel of metabolic treatments and drugs currently used to address this PGM1-linked cardiomyopathy to determine their effects (effectiveness vs. cardiotoxicity) on cardiac functionality and cardiac proteome (both holistic proteome profile changes and effects on pre-defined panels of biomarkers). The molecular and functional data will be analysed to highlight features of interest, such as new therapeutic targets, and lastly compiled in lucid reports aimed to help guiding the design of new therapeutic protocols tailored to the patient’s cardiac characteristics.
PGM1-linked cardiomyopathy has been chosen as first metabolic disease model in view of established protocols for cardiomyocytes and 3D-EHT generation, availability of patient-derived cell lines and available molecular data. However, this project aims to provide the proof-of-concept of our integrated HoPE technology platform for future applications to identify therapeutic treatments for a wide range of metabolic cardiomyopathies beyond PGM1-linked MCM.
