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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（申请人提供）：心血管疾病是发达国家的首要死因，晚期患者的预后非常差。充血性心力衰竭是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。尽管心血管疾病的治疗已取得显着进步，但其持续的不良预后使得开发新疗法成为必要。在心脏发育期间、正常生活期间和心血管疾病期间，受多种转录因子及其辅助因子（Nkx2、MEF2、NFAT、SRF、GATA、HDAC、HAT 和 TEF-1）控制的基因表达发生复杂的变化。已知如何在总体水平上调节某些但不是全部这些因子（例如 TEF-1）的活性。本提案中的研究将集中于确定 TEF-1 基因家族在心脏转录调控中的作用。这些研究将使用大鼠新生心肌细胞，这是一种完善的正常和患病心脏体外模型系统。这项资助的研究将解决以下假设：MCAT 位点、TEF-1 蛋白、其辅因子和其他心脏转录因子之间的相互作用是在正常和肥大心肌细胞中产生复杂的基因表达模式的关键。实验将 (1) 确定 TEF-1 是否调节正常和肥大心肌细胞中的内源性心脏基因表达（显性负蛋白，siRNA），(2) 确定 MCAT 核心序列是否通过影响 TEF-1 与其辅因子的相互作用来影响 MCAT 位点的活性，(3) 通过最先进的 MS/MS 分离新型 TEF-1 辅因子，以及 (4) 研究如何 TEF-1 辅因子（YAP65、TAZ、CK2）和 TEF-1 彼此相互作用并与其他心脏转录因子相互作用，以调节正常和肥厚条件下心肌细胞的基因表达。将使用的方法包括使用腺病毒载体表达显性失活 TEF-1 蛋白。这些分析将详细说明启动子对正常和患病心肌细胞中特定信号的反应机制，从而改善心脏病的治疗方法。