Cdk19-dependent transcriptional mechanisms in cardiac hypertrophy

项目摘要/摘要 慢性高血压引起的心力衰竭尽管长期存在，但仍严重影响人类健康 用目前的治疗方法进行管理。这在一定程度上是由于许多未知因素在背后 高血压性心力衰竭的发展。在动物模型中的研究已经证明了激活 心力衰竭的病理基因表达提示存在因果关系。这项提议的目标是 为了确定CDK19(和CDK8)的活性及其与介体的关联如何调节心脏基因的表达， 高血压压力超负荷应激时的左心室肥厚和左心功能障碍 使用经腹主动脉环扎术(TAB)或Ang-II治疗的小鼠。这是我们的假设，CDK19的活性是 依赖介体转录的完整高血压心衰功能反应所必需 监管。特定的目的是使用转基因的组合来检验这一假设 目的：1.确定小鼠对CDK8/19活性的需求 心肌细胞肥大和高血压反应。我们的工作假设是 CDK8/19驱动高血压心衰反应。根据我们的初步数据，我们预测在体内抑制 内源性CDK8/19与CCT251545和Senexin A联合应用可钝化TAB和Ang-II后的LVH 减少肥厚性心脏重构的治疗。为了解决CDK8和CDK19的结构作用，我们 制定目标2.确定CDK8/19对血管紧张素转换酶生理生化作用的影响 正常心脏功能所必需的心肌细胞。我们的工作假设是CDK8/19的丢失 导致心肌细胞功能障碍的原因是增强子的利用和基因表达失调。由于 CDK8和CDK19的潜在冗余作用，我们不预期CDK8(CDK8-CKO)的心脏敲除 或单用CDK19(CDK19-KO)可阻断左室肥厚或转录重塑。然而， 我们建议由于CDK8/19在中介中的作用，将需要对CDK8/19进行双基因敲除 应激心脏中应激反应增强剂的定位。这项提案的结果将确立 改变转录程序以应对高血压和心脏的潜在治疗靶点 失败了。

Project Summary/Abstract Heart failure due to chronic hypertension continues to significantly impact human health despite long term management with current treatments. This is in part due to the many unknown factors that underlie the development of hypertensive heart failure. Research in animal models has demonstrated activation of pathological gene expression in heart failure suggesting a causal relationship. The objective of this proposal is to determine how Cdk19 (and Cdk8) activity and association with Mediator regulates cardiac gene expression, left ventricular hypertrophy, and left ventricular dysfunction during hypertensive pressure overload stress in mice using transaortic banding (TAB) or Ang-II treatment. It is our hypothesis, that Cdk19 activity is necessary for the complete hypertensive HF functional response through Mediator-dependent transcriptional regulation. The specific Aims designed to test this hypothesis using a combination of genetically modified mice and pharmacological inhibitors are: Aim 1. Determine the requirement for Cdk8/19 activity in cardiomyocyte hypertrophic and hypertensive responses. It is our working hypothesis that the activity of Cdk8/19 drives hypertensive HF responses. Based on our preliminary data, we predict that in vivo inhibition of endogenous Cdk8/19 activity with CCT251545 and Senexin A will blunt both LVH after TAB and Ang-II treatment reducing hypertrophic cardiac remodeling. To address the structural role of Cdk8 and Cdk19, we developed Aim 2. Determine the impact of Cdk8/19 on the physiological and biochemical actions of cardiomyocytes that are necessary for normal cardiac function. Our working hypothesis is that loss of Cdk8/19 results in cardiomyocyte dysfunction due to dysregulated enhancer utilization and gene expression. Due to the potential redundant roles of Cdk8 and Cdk19, we don’t anticipate cardiac knockout of either Cdk8 (Cdk8-cKO) or Cdk19 (Cdk19-KO) alone will block left ventricular hypertrophy or transcriptional remodeling. However, we propose the double knockout of Cdk8/19 will be required due to the role of Cdk8/19 in Mediator localization to stress-responsive enhancers in stressed hearts. The outcomes of this proposal will establish potential therapeutic targets for modifying transcriptional programing in response to hypertension and heart failure.