Transcriptional regulation by TEF-1 in cardiac myocytes

TEF-1 在心肌细胞中的转录调控

基本信息

批准号：
7269994
负责人：
IAIN K FARRANCE
金额：
$ 28.16万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-08-01 至 2009-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7269994
关键词：
5-(4-hydroxy-3-methoxyphenyl)-5-phenylhydantoin ATP2A2 Actins Address Adenovirus Vector Affect Affinity Chromatography Arts Binding Binding Sites Biological Assay Biological Models Cardiac Cardiac Myocytes Cardiovascular Diseases Cardiovascular system Cause of Death Cells Class Co-Immunoprecipitations Complex Condition Congestive Heart Failure DNA DNA Sequencing Facility Defect Developed Countries Developing Countries Development Disease Dominant-Negative Mutation Embryo Enhancers Family Family member Gene Expression Gene Expression Regulation Gene Family Genes Genetic Transcription Grant Health Heart Heart Diseases Heart Hypertrophy Heart failure Histone Deacetylase Knockout Mice Life Myocardium Myosin Heavy Chains Neonatal Patients Pattern Process Proteins Rattus Regulation Research Role Signal Transduction Site Skeletal system Small Interfering RNA Staging Structure Time Transcriptional Regulation Troponin T United States cofactor day hemodynamics improved in vitro Model member myocyte-specific enhancer-binding factor 2 novel outcome forecast promoter research study response transcription factor

项目摘要

DESCRIPTION (provided by applicant): Cardiovascular diseases are the leading cause of death in developed countries, with a very poor prognosis for patients in advanced stages. Congestive heart failure, the end result of many cardiovascular problems is one of the most expensive health problems in the United States. Although there have been dramatic improvements in the treatment of cardiovascular diseases their continued poor prognosis makes the development of novel therapies necessary. During cardiac development, during normal life and during cardiovascular disease there are complex changes in gene expression controlled by multiple transcription factors and their cofactors (Nkx2, MEF2, NFAT, SRF, GATA, HDACs, HATs and TEF-1). It is known how the activity of some but not all of these factors, such as TEF-1 is regulated at a gross level. The research in this proposal will concentrate on determining the role of the TEF-1 gene family in transcriptional regulation in the heart. The studies will use rat neonatal cardiac myocytes, a well established in vitro model system of normal and diseased heart. The research in this grant will address the hypothesis that interactions between MCAT sites, TEF-1 proteins, their cofactors, and other cardiac transcription factors are key in generating the complex patterns of gene expression in normal and hypertrophic cardiac myocytes. The experiments will (1) determine if TEF-1 regulates endogenous cardiac gene expression in normal and hypertrophic cardiac myocytes (dominant negative proteins, siRNA), (2) determine if MCAT core sequence affects the activity of MCAT sites by influencing the interaction of TEF-1 with its cofactors, (3) isolate novel TEF-1 cofactors by state of the art MS/MS, and (4) study how the TEF-1 cofactors (YAP65, TAZ, CK2) and TEF-1 interact with each other and with other cardiac transcription factors to regulate gene expression in cardiac myocytes under normal and hypertrophic conditions. The approaches that will be used include expression of dominant negative TEF-1 proteins using adenoviral vectors. These analyses will detail the mechanisms of promoter response to specific signals in normal and diseased cardiac myocytes, leading to improved treatments for heart disease.

描述（由申请人提供）：心血管疾病是发达国家死亡的主要原因，晚期患者的预后非常差。充血性心力衰竭，许多心血管问题的最终结果是美国最昂贵的健康问题之一。尽管在心血管疾病的治疗方面取得了巨大改善，但他们的预后持续不佳使得需要新的疗法的发展。在心脏发育期间，在正常生活和心血管疾病期间，由多个转录因子及其辅因子（NKX2，MEF2，NFAT，NFAT，SRF，GATA，GATA，HATS，HATS，HATS和TEF-1）控制的基因表达发生了复杂的变化。众所周知，某些但不是全部这些因素（例如TEF-1）的活性如何在总级别调节。该提案中的研究将集中于确定TEF-1基因家族在心脏转录调节中的作用。这些研究将使用大鼠新生儿心肌细胞，这是一种正常和患病心脏的体外模型系统。该赠款中的研究将解决以下假设：MCAT位点，TEF-1蛋白，其辅助因子和其他心脏转录因子之间的相互作用是在正常和肥厚的心肌细胞中产生基因表达的复杂模式的关键。实验将（1）确定TEF-1在正常和肥厚心脏心肌细胞（主要负蛋白，siRNA）中是否调节内源性心脏基因表达，（2）确定MCAT核心序列是否会影响MCAT位点的活性，是否通过影响TEF-1的相互作用来影响TEF-1的相互作用（3）孤立的TEF-1 COFACTORS（3）COFACTORS（3）COFACTORS（3）COFACTORS（3）COFACTORS MS MS MS MS MS MS MS MAS，该Art and cofactors and MS MS（3）cofactors（3） TEF-1辅因子（YAP65，TAZ，CK2）和TEF-1相互相互作用，并与其他心脏转录因子相互作用，以调节正常和肥大性条件下心肌细胞中基因表达。将使用的方法包括使用腺病毒载体的显性阴性TEF-1蛋白的表达。这些分析将详细介绍启动子对正常和患病心肌细胞特定信号的反应机制，从而改善对心脏病的治疗方法。