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TCF7L2 isoforms in canonical Wnt signaling during cardiac hypertrophy and failure

心脏肥大和衰竭期间经典 Wnt 信号传导中的 TCF7L2 亚型

基本信息

批准号：
10209607
负责人：
Faqian Li
金额：
$ 49.08万
依托单位：
UNIVERSITY OF MINNESOTA
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/10209607
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 Hypertrophy 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.

项目总结