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The giant protein titin forms the elastic backbone of the sarcomere. It is extensively spliced and phosphorylated to adjust cardiac filling in health and disease. Here, we will combine our genetic with interventional animal models and human engineered heart tissue to dissect titin’s contribution to cardiac growth, metabolism, and filling and its relation to heart failure with preserved ejection fraction (HFpEF). Our focus on titin biomechanics and isoform expression in male versus female will contribute to an improved mechanistic understanding of HFpEF, assessment of diastolic dysfunction, and the adaptation of titin based stiffness as a basis for targeted therapy.
Graphical Abstract: Risk factors converge on cardiac splicing to adapt mechano-transduction, growth and filling. We will use mouse models and engineered heart tissue to study the role and therapeutic relevance of titin based mechanotransduction in HFpEF.