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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：
10593980
负责人：
Faqian Li
金额：
$ 49.19万
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/10593980
关键词：
Adult Affect Animal Model Armadillo Repeat 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 Play Population Study Primary idiopathic dilated cardiomyopathy Proliferating Protein Isoforms RNA Splicing Research Role Signal Transduction Single Nucleotide Polymorphism Site Specific qualifier value Stress System TCF Transcription Factor TCF7L2 gene Testing Tetanus Helper Peptide Tissue-Specific Gene Expression Tissues Transcriptional Activation Transgenic Mice Untranslated RNA Up-Regulation Variant WNT Signaling Pathway aorta constriction beta catenin cardiogenesis clinical translation differential expression effective therapy fetal gain of function heart function human disease human model loss of function mouse model neonatal mice new therapeutic target novel overexpression pharmacologic pressure prevent programs promoter recruit response targeted treatment therapy development transcription factor transmission process

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.

项目总结心力衰竭是一个主要的健康问题，其潜在的分子机制仍未明确。阻碍和拖延临床患者管理的有效和有针对性的治疗方法的开发。在许多心脏疾病的发病过程中，胎儿基因和发育信号被重新激活。这个经典的Wnt/β-catenin通路是最多样化的信号网络之一，已被认为与许多人类疾病以及发展的几乎方方面面。我们的数据显示，经典的 WnT/β-连环蛋白信号转导通路在人类和动物心力衰竭模型中发挥重要作用。然而，目前还不清楚 β-连环蛋白信号如何传递到转录机制以进行胎儿基因重编程。我们的数据已经揭示了TCF7L2亚型是组装β的主要和必要的核组织者- 连环蛋白介导的转录复合体。我们已经鉴定出心脏特异的主要TCF7L2亚型 TCF7L2在心脏发育不同阶段的表达及差异表达假说异构体决定了心脏Wnt信号的背景特异性基因靶点。更重要的是，胎儿TCF7L2 在衰竭的人类心脏中，异构体是活跃的。在这项提案中，我们将描述心脏特异的TCF7L2亚型以及它们在人类心脏中的目标基因。此外，我们将创建小鼠模型来确定TCF7L2是否是压力超负荷后发生心力衰竭所必需的，或者在以下情况下足以导致心力衰竭根据科赫的确定疾病病因的假设而过度表达。最后，我们会评价药物干预干预TCF7L2与β-连环蛋白相互作用是否可以预防心力衰竭压力过载或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亚型独特功能域的转导可以有效地防止甚至逆转心脏重塑和心力衰竭。