TCF7L2 Insoforms in Canonical Wnt Signaling During Cardiac Hpertrophy & Failure

TCF7L2 Insoforms 在心脏肥大过程中典型 Wnt 信号转导

基本信息

批准号：
10683483
负责人：
Faqian Li
金额：
$ 49.16万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10683483
关键词：
Adult Affect Animal Model Attenuated Binding Binding Proteins Cardiac Cardiac Myocytes Cells Clinical Code Complex Coronary Arteriosclerosis DNA Binding Domain Data Development Disabled Persons Disease Doxycycline Echocardiography Exons Failure Family Fibrosis Functional disorder Gene Expression Gene Targeting Genes Genetic Genetic Transcription Goals Health Heart Heart Abnormalities Heart Diseases Heart failure Histologic Human Hyperplasia Hypertrophy Intervention Knock-out Mediating Molecular Molecular Analysis Monitor Mus N-terminal Neonatal Non-Insulin-Dependent Diabetes Mellitus Nuclear Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Pharmacology Play Population Study Primary idiopathic dilated cardiomyopathy Protein Isoforms RNA Splicing Research Role Signal Transduction Single Nucleotide Polymorphism Site Stress System TCF Transcription Factor TCF7L2 gene Testing Tetanus Helper Peptide Tissue-Specific Gene Expression Tissues To specify Transcriptional Activation Transgenic Mice Untranslated RNA Up-Regulation Variant WNT Signaling Pathway base beta catenin cardiogenesis constriction differential expression effective therapy fetal heart function human disease human model loss of function mouse model neonatal mice new therapeutic target novel overexpression pressure prevent programs promoter recruit response targeted treatment therapy development transcription factor

项目摘要

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.

项目概要心力衰竭是一个主要的健康问题，其潜在的分子机制仍不清楚，阻碍和延迟临床患者管理的有效和有针对性的治疗方法的开发。在许多心脏病的发病过程中，胎儿基因和发育信号被重新激活。经典的 Wnt/β-catenin 通路是最多样化的信号网络之一，并且与许多人类疾病以及发展的几乎每个方面都表明了这一点。 Wnt/β-连环蛋白信号在人类和动物心力衰竭模型中发挥着关键作用，但目前尚不清楚。 β-连环蛋白信号如何传递到转录机器以进行胎儿基因重编程。揭示TCF7L2亚型是组装β-的主要和必需的核组织者我们已经确定了主要的心脏特异性 TCF7L2 亚型。 TCF7L2在心脏发育的不同阶段表达及差异表达同工型决定了心脏 Wnt 信号传导的特定基因靶点，更重要的是，胎儿 TCF7L2。异构体在人类心脏衰竭中具有活性。在本提案中，我们将分析心脏特异性的 TCF7L2 异构体。此外，我们将创建小鼠模型来确定TCF7L2是否存在。对于压力超负荷后发生心力衰竭是必要的，或者在以下情况下足以诱发心力衰竭：根据科赫的确定疾病病原体的假设，我们将过度表达。评估干扰 TCF7L2 与 β-catenin 相互作用的药物干预是否可以预防心力衰竭在压力过载或 TCF7L2 过度表达后，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 TCF7L2 亚型的独特功能域进行转导可以有效预防甚至逆转心脏重塑和心力衰竭。