TCF7L2 isoforms in canonical Wnt signaling during cardiac hypertrophy and failure

项目摘要 心力衰竭是一个主要的健康问题，其潜在的分子机制仍然不清楚， 阻碍和延迟了用于临床患者管理的有效和靶向疗法的开发。 在许多心脏疾病的发病过程中，胎儿基因和发育信号被重新激活。的 经典Wnt/β-catenin通路是最多样化的信号传导网络之一， 许多人类疾病以及发展的几乎每一个方面。我们的数据显示， Wnt/β-catenin信号在人类和动物心力衰竭模型中起着关键作用。但目前尚不清楚 β-catenin信号如何传递到转录机制进行胎儿基因重编程。我们的数据 揭示了TCF 7 L2亚型是组装β- 连环蛋白介导的转录复合物。我们已经确定了主要的心脏特异性TCF 7 L2亚型 在心脏发育的不同阶段表达，并假设TCF 7 L2的差异表达 同种型决定了心脏Wnt信号传导的背景特异性基因靶标。更重要的是，胎儿TCF 7 L2 同种型在衰竭的人类心脏中具有活性。在本提案中，我们将分析心脏特异性TCF 7 L2亚型 以及它们在人类心脏中的靶基因此外，我们将建立小鼠模型，以确定TCF 7 L2是否 是压力超负荷后心力衰竭发展所必需的，或足以诱导心力衰竭， 根据Koch的用于鉴定疾病的病原体的假设过表达。最后我们将 评价干预TCF 7 L2与β-catenin相互作用的药物干预是否可以预防心力衰竭 压力超负荷或TCF 7 L2过表达后。我们的目标是确定是否操纵β-连环蛋白信号 通过靶向心脏特异性TCF 7 L2亚型的独特功能结构域进行转导可以有效地预防 甚至逆转心脏重塑和心力衰竭。

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.