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.

项目摘要心力衰竭是一个主要的健康问题，基本的分子机制机制仍然不当定义，妨碍并延迟开发有效和破坏临床患者管理。在许多心脏病的发病机理中，胎儿基因和发育信号被重新激活典型的Wnt/β-catenininininin途径是最多样化的信号网络之一，已与许多人类疾病以及几乎所有发展方面的疾病。 Wnt/β-catenin信号传导在人类和动物的心力衰竭模型中起关键作用。 β-catenin信号如何传递到转录机制以重新降低我们的数据。已经揭示了TCF7L2同工型是组装β-的主要核组织者 Catenin介导的转录复合物。在心脏发育的不同阶段表达，并假设TCF7L2的差异表达同工型决定了心脏Wnt信号的上下文特异性基因靶标。同工型在人类心脏中活跃。他们的心脏中的目标基因。在压力超负荷后是否需要开发堡垒的堡垒失败或何时就足够的心力衰竭根据Koch的假设，我们会鉴定出疾病的疾病。评估药理干预TCF7L2是否与 - 连环蛋白Catent Cate Heart Bait的相互作用提出过载或TCF7L2过表达之后。通过靶向心脏特异性TCF7L2同工型的靶向域的转导可以有效防止甚至反向CardiACC重塑和心力衰竭。