KLF15 as novel regulator of cardiomyocyte biology

KLF15 作为心肌细胞生物学的新型调节剂

基本信息

批准号：
7494563
负责人：
MUKESH Kumar JAIN
金额：
$ 38.63万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-01 至 2011-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7494563
关键词：
Adult Affect Aortic Valve Stenosis Biological Assay Biology Cardiac Cardiac Myocytes Cell Size Cessation of life Condition Congestive Heart Failure Development Dilatation - action Embryonic Development Embryonic Heart Event Exhibits Family Fibrosis Foundations Gelshift Analysis Gene Expression Genes Glutathione S-Transferase Goals Heart Heart Hypertrophy Heart failure Human Hypertrophy In Vitro Knockout Mice Lead Left Mechanics Mediating Mediator of activation protein Molecular Morbidity - disease rate Muscle Cells Neonatal Numbers Pathologic Pathological Dilatation Pathway interactions Patients Phenotype Phenylephrine Post-Translational Protein Processing Process Protein Biosynthesis Protein Overexpression Rattus Rodent Rodent Model Role Screening procedure Secondary to Signal Pathway Societies Stress Tissues Ventricular Weight base cDNA Library chromatin immunoprecipitation fetal gain of function hemodynamics in vivo inhibitor/antagonist insight interest loss of function member mortality novel novel therapeutics postnatal pressure promoter response size transcription factor

项目摘要

DESCRIPTION (provided by applicant): Hypertrophy of cardiomyocytes is a common response to mechanical and hemodynamic stress and is characterized by an increase in cell size, protein synthesis, and re-expression of fetal genes. Left untreated, cardiac hypertrophy can ultimately lead to congestive heart failure - a leading cause of morbidity and mortality in our society. Studies over the past two decades have identified a number of signaling pathways and molecular mediators (e.g. GATA4) that promote the hypertrophic response. However, much less is known about the negative regulators of the process. Studies in this proposal investigate a novel molecular factor that inhibits cardiac hypertrophy termed KLF15. KLF15 is a member of the Kruppel-like family of transcription factors that are known to regulate key aspects of cellular development and function. KLF15 expression is low in the embryonic heart and induced in the postnatal period. Conversely, KLF15 expression is reduced by pressure-induced cardiac hypertrophy in vivo and by pro-hypertrophic agents in vitro. Consistent with these observations, KLF15 expression is reduced in human heart tissues from patients with aortic stenosis. Adenoviral overexpression of KLF15 in neonatal rat ventricular myocytes reduces basal and phenylephrine induced increases in cell size, protein synthesis, and gene expression. Multiple lines of evidence suggest that these effects are secondary to inhibition of the pro- hypertrophic factor GATA4. Finally, KLF15 null mice have been generated. Studies to date indicate that in response to pressure overload KLF15 null mice exhibit an eccentric form of pathologic remodeling. The goals of this proposal are: (1) To comprehensively study the effect of KLF15 on cardiac gene expression and function by gain and loss of function approaches; (2) To determine the molecular basis for KLF15's ability to inhibit myocyte hypertrophy in vitro; (3) To determine the functional consequences of altering KLF15 levels on GATA4 mediated hypertrophy in vivo. The results of these studies will provide insights regarding the role of KLF15 as an inhibitor of cardiac hypertrophy and may provide the foundation for novel therapeutic strategies in the treatment of heart failure.

描述（由申请人提供）：心肌细胞肥大是对机械和血流动力学应激的常见反应，其特征是细胞大小、蛋白质合成和胎儿基因重新表达的增加。如果不及时治疗，心脏肥大最终会导致充血性心力衰竭——这是我们社会发病和死亡的主要原因。过去二十年的研究已经确定了许多促进肥大反应的信号通路和分子介质（例如 GATA4）。然而，人们对这一过程的负调节剂知之甚少。该提案中的研究调查了一种名为 KLF15 的抑制心脏肥大的新型分子因子。 KLF15 是 Kruppel 样转录因子家族的成员，已知该转录因子可调节细胞发育和功能的关键方面。 KLF15 表达在胚胎心脏中较低，并在出生后诱导。相反，体内压力诱导的心脏肥大和体外促肥大剂可降低 KLF15 的表达。与这些观察结果一致，主动脉瓣狭窄患者的人类心脏组织中 KLF15 表达减少。新生大鼠心室肌细胞中 KLF15 的腺病毒过度表达可减少基础和去氧肾上腺素诱导的细胞大小、蛋白质合成和基因表达的增加。多种证据表明这些效应是抑制促肥大因子 GATA4 的继发因素。最后，产生了KLF15无效小鼠。迄今为止的研究表明，为了应对压力超负荷，KLF15 缺失小鼠表现出一种奇怪的病理重塑形式。该提案的目标是：（1）通过功能获得和丧失的方法全面研究KLF15对心脏基因表达和功能的影响；（2）确定KLF15体外抑制心肌细胞肥大能力的分子基础； (3) 确定改变 KLF15 水平对 GATA4 介导的体内肥大的功能影响。这些研究的结果将提供有关 KLF15 作为心脏肥大抑制剂的作用的见解，并可能为治疗心力衰竭的新治疗策略提供基础。