Mechanisms of YY1 Inhibition of Cardiac Hypertrophy

描述（由申请人提供）：心力衰竭是美国最昂贵的医疗问题，也是导致死亡和残疾的主要原因。虽然针对心力衰竭治疗的药物抑制剂在治疗上是有益的，但心力衰竭的频率仍然在增加，需要额外的靶点。我们的长期目标是确定转录因子YY1防止病理性心脏肥厚的分子机制，并为预防心脏病提供有价值的靶点。YY1是一种普遍存在的转录因子，调节多种基因的表达。YY1已被证明主要是肌肉基因的抑制因子。我们有强有力的初步数据表明YY1可以防止伴随心肌肥大的细胞变化。YY1通过结合和保留细胞核II类组蛋白去乙酰化酶（hdac）来阻止胎儿对α和β肾上腺素能刺激的基因表达上调。本应用的目的是：（目的一）确定YY1在各种肥厚受体激动剂作用下阻止hdac 4和hdac 5核输出的机制；（Aim II）分析YY1在各种肥厚刺激下与胎儿基因启动子的相互作用（Aim III）在病理性心脏肥厚的体内模型系统中表征YY1过表达的影响。目的1通过分析YY1-HDAC相互作用域来实现；将含有相互作用结构域的构建体转染到新生儿心肌细胞中，分析基因表达、细胞肥大和hdac 4和hdac 5的定位。Aim II将通过染色质免疫沉淀YY1和各种胎儿基因启动子响应肥厚刺激来实现。目的四通过建立YY1过表达的条件转基因小鼠模型来实现。这些动物将通过植入含有肥厚激动剂的微型渗透泵诱导肥厚，并分析心脏功能和细胞肥厚的变化。从这些研究中揭示的数据将迅速推进我们对病理性心肌肥厚发展的信号成分的理解。

DESCRIPTION (provided by applicant): Heart failure is the most expensive medical problem in the United States, and a major cause of death and disability. Although pharmacological inhibitors targeted to the treatment of heart failure are therapeutically beneficial, heart failure is still increasing in frequency, and additional targets are needed. Our long term goal is to define the molecular mechanism(s) by which the transcription factor YY1 protects against pathologic cardiac hypertrophy and to provide valuable targets for the prevention of cardiac disease. YY1 is an ubiquitous transcription factor that regulates expression of multiple genes. YY1 has been shown to be mostly a represser of muscle genes. We have strong preliminary data showing that YY1 prevents the cellular changes that accompany cardiac hypertrophy. YY1 prevents up-regulation of the fetal isoforms of gene expression in response to alpha and beta adrenergic stimulation by binding to and retaining in the nucleus class II histone deacetylases (HDACs). The goals of this application are to: (Aim I) identify the mechanism by which YY1 prevents HDACs 4 and 5 nuclear export in response to various hypertrophic agonists; (Aim II) analyze the interaction of YY1 with fetal gene promoters in response to various hypertrophic stimuli (Aim III) characterize the effect of YY1 over-expression in an in vivo model system of pathological cardiac hypertrophy. Aim I will be achieved by analyzing YY1-HDAC interaction domains; constructs containing the interaction domains will be transfected into neonate cardiac myocytes and gene expression, cellular hypertrophy and HDACs 4 and 5 localization will be analyzed. Aim II will be achieved through chromatin immunoprecipitation of YY1 and the various fetal gene promoters in response to hypertrophic stimuli. Aim IV will be achieved by creating a conditional transgenic mouse model of YY1 over-expression. Hypertrophy will be induced in these animals by implantation of mini-osmotic pumps containing hypertrophic agonists, and heart function and changes in cellular hypertrophy will be analyzed. The data revealed from these studies will rapidly progress our understanding of the signaling components responsible for the development of pathologic cardiac hypertrophy.