Uncovering new cardiac biology by the application of novel techniques in the adult heart

Abstract

The heart is a vital organ that pumps blood though the body, thereby supplying the organs with enough oxygen and nutrients. Since the heart has such a crucial function, heart diseases and failure lead to a significant decline in quality of life and early mortality. Current treatments are aimed at reducing the symptoms of heart diseases. However, these treatments do not cure the disease and most patients with a heart disease die early. It is therefore imperative that we increase our understanding of biological processes that occur in a normal and a diseased heart. In this thesis, we applied various new techniques to the adult heart for the first time to increase fundamental knowledge of cardiac biology and disease. Using genome editing with CRISPR/Cas9 and single-cell RNA sequencing, we have been able to study the heart in a resolution that was previously not possible. This allowed us to make various discoveries. In the normal heart, we identified a new biological player, a small protein we named smORF4. Results indicated that smORF4 could have an important function in controlling heart contraction. During disease, in particular a heart infarct, application of single-cell RNA sequencing enabled us to identify 2 genes that seem to play an important role in how the heart functions after the infarct. Altogether, we think that the datasets we have generated with these new techniques can be used by researchers to gain a better understanding of heart diseases and hopefully lead to new and better therapies.