Inherited cardiomyopathies are clinically heterogeneous: age of onset and disease-severity differ greatly between patients with the exact same gene mutation. The mechanisms that underlie the variation in disease susceptibility are unknown.
Pilot data of Dosis suggest an important role for secondary disease-modifiers such as additional (epi)genetic variations, environmental disease triggers, and an age-related decline in protein quality control (PQC). The PQC system prevents onset of cardiomyopathies by suppressing the accumulation of toxic proteins in cardiomyocytes. Moreover, cardiomyopathy severity is attenuated by the stimulation of protein degradation pathways. Thus, a healthy PQC system keeps mutant expression below the toxic dose. In addition, mutation location in a gene may determine disease susceptibility due to specific mutation-induced changes in protein structure, which alter PQC recognition, and affect incorporation into the sarcomere.
Our hypothesis is that the clinical variability in cardiomyopathy is determined by:
To unravel the complex cardiomyopathy pathophysiology, we believe in a tight collaboration between the different actors involved in cardiomyopathies, including (clinical) geneticists, cardiologists, cell biologists and physiologists. Dosis bundles expertise within the different research fields and links clinical studies with mechanistic insights obtained from molecular and functional studies in human cardiac muscle samples, cell systems and animal models, which cover the initial but also the advanced stages of inherited cardiomyopathies. Dosis is directed at understanding the path a mutation needs to travel to become toxic, and at testing novel therapies in experimental model systems.
“Why is the onset of the disease a lot earlier in one person and does the heart degenerate much faster in the other? That is what we want to eludicate in the coming 4 years”, says researcher Jolanda van der Velden. “We think there is a connection between the initial genetical mutation and other factors in the human body. That is why we look for additional causes that make the initial genetical mutation to cause harm or less harm”
The researchers also investigate the renewal system that fixes the proteins in the heart muscle cells. This system derails faster in some people when they get older compared to others. Because of this pathologic proteins accumulate in too high doses in the heart muscle cell. Healthy proteins are vital for proper contraction of heart muscle cells. When the dose of a pathologic protein exceeds a certain limit, it causes heart muscle disease.
In this research project the renewal system of proteins in heart muscle cells are investigated. New agents were developed that can stimulate the renewal system. The researchers aim to stimulate the renewal system of the heart in order to prevent or slow down the progression of heart muscle diseases. In this way they strive to develop new therapeutic agents for heart muscle diseases.
The Dutch Heart Foundation invests €1.5 million in this research that will run from 2015-2019. The lead investigators are prof. dr. Jolanda van der Velden (Physiology VUmc) and Rudolf de Boer, professor of Cardiology at the UMCG Groningen.