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: 10544809
• 负责人: David Alan Kass
• 金额: $ 43.29万
• 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 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10544809
• 关键词: Agonist; Arrhythmia; Autophagocytosis; Biology; Biopsy; Blood; Blood Vessels; Cardiac Myocytes; Cardiomyopathies; Cyclic AMP-Dependent Protein Kinases; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Data; Disease; Enzymes; Estrogens; Female; Goals; Health; Heart; Heart Diseases; Heart failure; Human; Impairment; Metabolic syndrome; Methods; MicroRNAs; Molecular Target; Natriuretic Peptides; Nitric Oxide; Obesity; Oxidative Stress; Pathologic; Pathway interactions; Patients; Postmenopause; Proteins; Proteomics; Quality Control; Regulation; Research; Role; Second Messenger Systems; Signal Pathway; Signal Transduction; Stress; Therapeutic Uses; Transcriptional Regulation; Work; cGMP-dependent protein kinase Ibeta; cardiac muscle disease; comorbidity; improved; innovation; invention; mechanotransduction; multicatalytic endopeptidase complex; nano; novel; personalized approach; phosphoric diester hydrolase; programs; protective effect; response; therapeutically effective; 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.

该项目的目标是重新发明有关监管，目标， 特别是蛋白激酶G（PKG）活化的翻译用途， 心肌病PKG是由第二信使环GMP（cGMP）激活的主要酶 也是血管张力的重要调节器它在心肌细胞中的作用 有争议，但越来越多的证据表明，刺激PKG提供了一个有效的抗压力， 病理生理学制动，对抗促肥大/纤维化信号传导，机械感测和 心律失常，改善舒张功能。我们实验室的新数据显示， 深刻影响microRNA的形成，蛋白质质量控制和自噬。环GMP是 由一氧化氮或利钠肽信号通路产生。虽然两者都有很长的 被视为可互换的，我们最近的工作表明，在他们的作用， 在心肌细胞中的调节。它们在纳米结构域中运作，由特定的磷酸- 二酯酶;特别是分别靶向NO和NP刺激的cGMP的PDE 5和PDE 9。因此如何 一个人有效地激活PK取决于疾病状况， 产生，参与的PDE，甚至PKG的翻译后状态。比如说， 氧化应激，抑制NO刺激的cGMP也氧化PKG，我们发现这降低了其 保护作用，同时也改变其对激动剂的反应。雌激素耗竭损害 在女性中NO刺激cGMP，损害依赖于该途径的PKG激活策略。 这个R35计划开发了四个创新的研究计划，旨在最终提高我们的 PKG活化的治疗用途：1）解剖纳米结构域对照，定义蛋白质配偶体， 选择性PKG激酶靶点，它们在不同疾病中的动力学，以及它们如何能够更好地 2）确定合并症，如肥胖，代谢综合征， 绝经后限制PKG激活策略，并开发规避它们的方法; 3） 发现PKG激活提供益处的新信号传导，包括在 自噬、蛋白体运输、病理性机械感应和转录控制;以及4） 使用新的蛋白质组学方法开发PKG蛋白型，应用于人类心脏活检和血液。 通过这项工作，我们的目标是改变PKG治疗心脏病的概念， 生物学来获得有效的个性化方法。

项目成果

Acute Enhancement of Cardiac Function by Phosphodiesterase Type 1 Inhibition.

• DOI: 10.1161/circulationaha.117.030490
• 发表时间: 2018-10-30
• 期刊: Circulation
• 影响因子: 37.8
• 作者: Hashimoto T;Kim GE;Tunin RS;Adesiyun T;Hsu S;Nakagawa R;Zhu G;O'Brien JJ;Hendrick JP;Davis RE;Yao W;Beard D;Hoxie HR;Wennogle LP;Lee DI;Kass DA
• 通讯作者: Kass DA

TSC2 S1365A mutation potently regulates CD8+ T cell function and differentiation and improves adoptive cellular cancer therapy.

• DOI: 10.1172/jci.insight.167829
• 发表时间: 2023-11-08
• 期刊: JCI INSIGHT
• 影响因子: 8
• 作者: Patel, Chirag H.;Yi, Dong;Koleini, Navid;Wang, Xiaoxu;Dunkerly-Eyring, Brittany L.;Wen, Jiayu;Ranek, Mark J.;Bartle, Laura M.;Henderson, Daniel B.;Sagert, Jason;Kass, David A.;Powell, Jonathan D.
• 通讯作者: Powell, Jonathan D.

Response by Kass et al to Letter Regarding Article, "Chronic Atrial and Ventricular Pacing in the Mouse: Application to Model Cardiac Dyssynchrony and Resynchronization in Heart Failure".

Kass 等人对有关文章“小鼠慢性心房和心室起搏：在心力衰竭中心脏不同步和再同步模型的应用”的信件的回应。

• DOI: 10.1161/circheartfailure.119.006094
• 发表时间: 2019
• 期刊: Circulation. Heart failure
• 作者: Kass,DavidA;Nakagawa,Ryo;Ståhlberg,Marcus
• 通讯作者: Ståhlberg,Marcus

Transient receptor potential canonical type 6 (TRPC6) O-GlcNAcylation at Threonine-221 plays potent role in channel regulation.

• DOI: 10.1016/j.isci.2023.106294
• 发表时间: 2023-03-17
• 期刊: ISCIENCE
• 影响因子: 5.8
• 作者: Mishra, Sumita;Ma, Junfeng;McKoy, Desirae;Sasaki, Masayuki;Farinelli, Federica;Page, Richard C.;Ranek, Mark J.;Zachara, Natasha;Kass, David A.
• 通讯作者: Kass, David A.

Protein S-Nitrosylation Controls Glycogen Synthase Kinase 3β Function Independent of Its Phosphorylation State.

• DOI: 10.1161/circresaha.118.312789
• 发表时间: 2018-05-25
• 期刊: Circulation research
• 影响因子: 20.1
• 作者: Wang SB;Venkatraman V;Crowgey EL;Liu T;Fu Z;Holewinski R;Ranek M;Kass DA;O'Rourke B;Van Eyk JE
• 通讯作者: Van Eyk JE