Cdk19-dependent transcriptional mechanisms in cardiac hypertrophy

心脏肥大中 Cdk19 依赖性转录机制

• 批准号: 10216549
• 负责人: Chad E Grueter
• 金额: $ 15.45万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-15 至 2023-05-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10216549
• 关键词: Acute Myelocytic Leukemia; Address; Adult; Affect; Angiotensins; Animal Model; Attenuated; Biochemical; Cardiac; Cardiac Myocytes; Chronic; Clinical Trials; Complex; Coupling; DNA Binding; DNA Polymerase II; DNA-Directed RNA Polymerase; Data; Development; Disease; Enhancers; Functional disorder; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Enhancer Element; Genetic Transcription; Goals; Growth; Health; Heart; Heart Diseases; Heart Hypertrophy; Heart failure; Human; Hypertension; In Vitro; Knock-out; Knockout Mice; Left Ventricular Dysfunction; Left Ventricular Hypertrophy; Longitudinal Studies; Mediating; Mediator of activation protein; Mission; Modeling; Molecular; Mus; Myocardial dysfunction; Outcome; Pathologic; Pathway interactions; Patients; Pharmacology; Phase; Phosphotransferases; Physiological; Regulation; Research; Risk; Risk Factors; Rodent Model; Role; Severities; Signal Transduction; Specificity; Stress; Structure; Technology; Testing; Transcriptional Regulation; United States National Institutes of Health; Work; base; cell type; cyclin C; design; heart function; human model; in vivo; inhibitor/antagonist; malignant breast neoplasm; next generation sequencing; novel; novel strategies; novel therapeutic intervention; paralogous gene; pressure; prevent; programs; promoter; recruit; response; therapeutic target; tool; transcription factor

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.

项目概要/摘要 尽管长期来看，慢性高血压引起的心力衰竭仍然对人类健康产生重大影响 使用当前治疗进行管理。这部分是由于许多未知因素造成的 高血压性心力衰竭的发展。动物模型研究表明， 心力衰竭中的病理基因表达表明存在因果关系。该提案的目标是 确定 Cdk19（和 Cdk8）活性以及与 Mediator 的关联如何调节心脏基因表达， 高血压超负荷应激期间左心室肥厚和左心室功能障碍 使用经主动脉束带 (TAB) 或 Ang-II 治疗的小鼠。我们的假设是，Cdk19 活性是 通过介导依赖性转录对完整的高血压心力衰竭功能反应是必需的 规定。旨在使用转基因组合来检验这一假设的具体目标 小鼠和药物抑制剂是： 目标 1. 确定 Cdk8/19 活性的要求 心肌细胞肥大和高血压反应。我们的工作假设是 Cdk8/19 驱动高血压心力衰竭反应。根据我们的初步数据，我们预测体内抑制 CCT251545 和 Senexin A 的内源性 Cdk8/19 活性将在 TAB 和 Ang-II 后减弱 LVH 减少肥厚性心脏重塑的治疗。为了解决 Cdk8 和 Cdk19 的结构作用，我们 制定的目标 2. 确定 Cdk8/19 对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 由于增强子利用和基因表达失调而导致心肌细胞功能障碍。由于 由于 Cdk8 和 Cdk19 的潜在冗余作用，我们预计不会出现 Cdk8 (Cdk8-cKO) 的心脏敲除 或单独使用 Cdk19 (Cdk19-KO) 即可阻断左心室肥厚或转录重塑。然而， 由于Cdk8/19在Mediator中的作用，我们建议需要对Cdk8/19进行双敲除 定位于应激心脏中的应激反应增强子。该提案的结果将确定 改变转录编程以应对高血压和心脏病的潜在治疗靶点 失败。

项目成果

Investigating the Therapeutic Potential of Cdk8 Small Molecule Inhibitors to Prevent Pathological Cardiac Remodeling and Heart Failure.

研究 Cdk8 小分子抑制剂预防病理性心脏重塑和心力衰竭的治疗潜力。

• 发表时间: 2022
• 期刊: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
• 作者: Oppman,AlexisM;Gardner,RichardN;Martins,Ines;Minerath,RachelA;Hall,DuaneD;Grueter,ChadE
• 通讯作者: Grueter,ChadE