TCF7L2 isoforms in canonical Wnt signaling during cardiac hypertrophy and failure

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Project summary Heart failure is a major health problem and its underlying molecular mechanisms remain poorly defined, hampering and delaying the development of effective and targeted therapies for clinical patient management. During the pathogenesis of many heart diseases, fetal genes and developmental signals are re-activated. The canonical Wnt/β-catenin pathway is one of the most diverse signaling networks and has been implicated in many human diseases as well as almost every aspect of development. Our data have revealed that canonical Wnt/β-catenin signaling plays a key role in human and animal models of heart failure. However, it is not clear how β-catenin signaling is transmitted to the transcriptional machinery for fetal gene reprograming. Our data has revealed that TCF7L2 isoforms are the major and essential nuclear organizers that assemble the β- catenin-mediated transcriptional complex. We have identified major cardiac-specific TCF7L2 isoforms expressed in different stages of heart development and hypothesize that differential expression of TCF7L2 isoforms dictates the context-specific gene targets of cardiac Wnt signaling. More importantly, fetal TCF7L2 isoforms are active in failing human hearts. In this proposal, we will profile cardiac-specific TCF7L2 isoforms and their target genes in human hearts. Moreover, we will create mouse models to determine whether TCF7L2 is necessary for heart failure development after pressure overload or sufficient to induce heart failure when overexpressed according to Koch’s postulates for identifying the causative agents of a disease. Finally, we will evaluate if pharmacologic intervention to interfere TCF7L2 interaction with β-catenin can prevent heart failure after pressure overload or TCF7L2 overexpression. Our goal is to determine if manipulating β-catenin signal transduction by targeting unique function domains of cardiac-specific TCF7L2 isoforms can efficiently prevent or even reverse cardiac remodeling and heart failure.