Leveraging Protein Kinase G-1 Nanodomain Control and Molecular Targeting to Enhance its Therapeutic Use Against Myocardial Disease

利用蛋白激酶 G-1 纳米结构域控制和分子靶向增强其对心肌疾病的治疗作用

• 批准号: 9244504
• 负责人: David Alan Kass
• 金额: $ 99.49万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9244504
• 关键词: Agonist; Arrhythmia; Autophagocytosis; Biology; Biopsy; Blood; Blood Vessels; Cardiac Myocytes; Cardiomyopathies; Comorbidity; Cyclic AMP-Dependent Protein Kinases; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Data; Depressed mood; Disease; Enzymes; Estrogens; Female; Goals; Health; Heart; Heart Diseases; Heart failure; Human; Impairment; Metabolic syndrome; Methods; MicroRNAs; Molecular Target; Myocardium; Myopathy; Natriuretic Peptides; Nitric Oxide; Obesity; Oxidative Stress; Oxides; Pathologic; Pathway interactions; Patients; Postmenopause; Proteins; Proteomics; Quality Control; Regulation; Research; Role; Second Messenger Systems; Signal Pathway; Signal Transduction; Stress; Therapeutic Uses; Transcriptional Regulation; Treatment Efficacy; Work; base; cGMP-dependent protein kinase Ibeta; improved; innovation; mechanotransduction; multicatalytic endopeptidase complex; nano; novel; personalized approach; phosphoric diester hydrolase; programs; protective effect; response; tool; trafficking

The goal of this project is to re-invent concepts regarding the regulation, targeting, and particularly the translational use of protein kinase G (PKG) activation for the goal of treating myocardial disease. PKG is the primary enzyme activated by the second messenger cyclic GMP (cGMP) and a prominent regulator of vascular tone. Its role in the cardiomyocyte has been more controversial, but growing evidence shows that stimulating PKG provides a potent anti-stress and pathophysiological brake, countering pro- hypertrophic/fibrotic signaling, mechano-sensing and arrhythmia, and improving diastolic function. New data from our lab now shows it can also profoundly impact microRNA formation, protein quality control, and autophagy. Cyclic GMP is generated by either a nitric oxide or natriuretic peptide signaling-pathway. While both have long been viewed as interchangeable, our recent work shows prominent differences in their role and regulation in the cardiomyocyte. They operate in nano-domains regulated by specific phospho- diesterases; notably PDE5 and PDE9 that target NO and NP stimulated cGMP, respectively. Thus, how one activates PK effectively depends upon the disease condition and thus how cGMP is being generated, which PDEs are involved, and even the post-translational state of PKG. For example, oxidative stress, which depresses NO-stimulated cGMP also oxidizes PKG, which we showed reduces its protective effects while also altering its response to agonists. Estrogen depletion impairs NO-stimulated cGMP in females, compromising PKG activation strategies dependent on this pathway. This R35 program develops four innovative research programs aimed at ultimately improving our therapeutic use of PKG activation: 1) Dissect nano-domain controls, defining protein partners, selective PKG kinase targets, their dynamics in varying diseases, and how they can be more effectively regulated; 2) Identify how co-morbidities such as obesity, metabolic syndrome, and post- menopause limit PKG activation strategies, and develop methods to circumvent them; 3) Discover novel signaling by which PKG activation provides benefit, including new roles in autophagy, proteosome trafficking, pathological mechanosensing and transcriptional controls; and 4) Develop a PKG proteotype using new proteomic methods applied to human heart biopsies and blood. Through this work, we aim to transform concepts of PKG therapy for heart disease, based on its biology to derive an effective personalized approach.

该项目的目的是重新发明有关法规，定位和目标的概念 特别是蛋白激酶G（PKG）激活的转化使用以治疗目的 心肌疾病。 PKG是由第二信使环GMP（CGMP）激活的主要酶 以及著名的血管音调调节剂。它在心肌细胞中的作用更多 有争议的，但越来越多的证据表明，刺激PKG提供了有效的反压力和 病理生理制动器，反营养/纤维化信号传导，机械感应和 心律不齐，并改善舒张功能。我们实验室的新数据现在表明它也可以 深刻影响microRNA形成，蛋白质质量控​​制和自噬。循环GMP是 由一氧化氮或亚位钠肽信号通道产生。虽然两者都有很长的 被认为是可互换的，我们最近的工作表明其角色显着差异 心肌细胞中的调节。它们在特定磷酸化调节的纳米域中运行 二酯酶；靶向NO和NP的PDE5和PDE9分别刺激了CGMP。因此，如何 一个人有效激活PK取决于疾病状况，因此CGMP的状况如何 生成的PDE所涉及的，甚至是PKG的翻译后状态。例如， 降低未刺激的CGMP的氧化应激也将PKG氧化，我们显示的氧化应激降低了它的氧化应激。 保护作用，同时也改变了对激动剂的反应。雌激素耗尽损害 女性未刺激的CGMP，损害PKG激活策略取决于该途径。 该R35计划开发了四个创新研究计划，旨在最终改善我们的 PKG激活的治疗用途：1）剖析纳米域控制，定义蛋白质伴侣， 选择性PKG激酶靶标，它们在各种疾病中的动态以及如何成为更多 有效监管； 2）确定肥胖，代谢综合征等合并症如何 更年期后限制了PKG激活策略，并开发了规避它们的方法； 3） 发现PKG激活提供好处的新颖信号，包括新角色 自噬，蛋白质体运输，病理机械感应和转录控制；和4） 使用应用于人心脏活检和血液的新蛋白质组学方法开发PKG蛋白质型。 通过这项工作，我们旨在根据其基于其心脏病的PKG疗法的概念 生物学得出有效的个性化方法。