Working Group Gotthardt

Research Focus

  • Heart Failure (HFpEF)
  • Mechanotransduction
  • Drug development

 

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The Gotthardt Lab

Cardiac signaling pathways converge on the splice factor RBM20 that regulates isoform expression of sarcomeric proteins. Among them, titin determines the elastic properties and thus cardiac filling with important functions in development and disease.

In Germany, heart failure keeps a top spot in mortality statistics although prevention and therapy have continuously been improved. The current classification differentiates Heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF). For HFpEF, a disease that predominantly affects women and amounts to 50% of all heart failure patients, there is currently no targeted therapy.
We aim to improve this situation by developing an improved understanding of factors that govern the elastic properties of the cardiac ventricle and mechanotransduction pathways that chance mechanical properties in health and disease. We focus on the sarcomeric protein titin and its splice factor RBM20 that affects titin’s spring region.
Only recently has the role of alternative splicing in cardiovascular disease been appreciated with mutations in the splice factor RBM20 occurring in up to 3% of patients with idiopathic cardiomyopathy. So far, a systematic approach to harness exon-level information for improved diagnosis and therapy has been hampered by the lack of transcriptome wide sequence information, suitable reporter assays, and computational tools. Utilizing existing clinical and molecular patient information in addition to patient samples and induced pluripotent stem cells (iPSCs), we will establish a comprehensive workflow of RNA guided molecular functional diagnostics and therapy of cardiac disease. This includes the analysis of splice factor function and regulation as a basis for therapeutic decisions and the development and evaluation of splice directed therapeutics in engineered heart muscle (EHM) from patient derived differentiated iPSCs towards personalized diagnosis and therapy.