A systems and translational approach to titin dynamics in HFpEF (B04)

巨大的蛋白质Titin形成了肌节的弹性脊椎。它被广泛地剪接和磷酸化，以调节健康和疾病中的心脏充盈。在这里，我们将结合我们的基因与介入性动物模型和人类工程化心脏组织来剖析Titin对心脏生长、新陈代谢和充盈的贡献，以及它与射血分数保留的心力衰竭(HFpEF)的关系。我们关注肌动蛋白在男性和女性中的生物力学和异构体表达，将有助于更好地理解HFpEF的机制，评估舒张期功能障碍，并适应以肌动蛋白为基础的僵硬作为靶向治疗的基础。

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.