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，也是死亡和残疾的主要原因。尽管靶向治疗心力衰竭的药理学抑制剂在治疗上是有益的，但心力衰竭的频率仍在增加，并且需要额外的靶点。我们的长期目标是确定转录因子YY 1保护病理性心脏肥大的分子机制，并为预防心脏疾病提供有价值的靶点。YY 1是一种普遍存在的转录因子，调节多个基因的表达。YY 1已被证明主要是肌肉基因的阻遏物。我们有强有力的初步数据表明，YY 1可以防止伴随心脏肥大的细胞变化。YY 1通过结合并保留在细胞核中的II类组蛋白脱乙酰酶（HDAC）来防止响应于α和β肾上腺素能刺激的基因表达的胎儿同种型的上调。本申请的目的是：（目的I）鉴定YY 1响应于各种肥大激动剂而阻止HDAC 4和5核输出的机制;（目的II）分析YY 1响应于各种肥大刺激而与胎儿基因启动子的相互作用（目的III）表征YY 1过表达在病理性心脏肥大的体内模型系统中的作用。目的通过分析YY 1-HDAC相互作用结构域实现I;将含有相互作用结构域的构建体转染到新生心肌细胞中，并分析基因表达、细胞肥大和HDAC 4和5定位。目的II将通过染色质免疫沉淀YY 1和各种胎儿基因启动子响应肥大刺激。目的IV通过建立YY 1过表达的条件性转基因小鼠模型来实现。通过植入含有肥大激动剂的微型渗透泵诱导这些动物的肥大，并分析心脏功能和细胞肥大的变化。这些研究揭示的数据将迅速推进我们对病理性心脏肥大发展的信号传导成分的理解。

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.