O-GlcNAcylation and YAP: Defining a novel pathway in heart failure

O-GlcNAcylation 和 YAP：定义心力衰竭的新途径

基本信息

批准号：
10507138
负责人：
Mahaa Umapathi
金额：
$ 17.17万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-17 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10507138
关键词：
Accounting Address American Animals Area Arrhythmia Award Bioinformatics Biological Assay Biology Carbohydrates Cardiac Cardiac Myocytes Cardiac health Cardiomyopathies Cardiovascular system Cells Chronic Data Depressed mood Development Development Plans Diagnosis Disease Elements Enzymes Evaluation Exhibits Exposure to Gene Expression Genes Genetic Genetic Models Genetic Transcription Glycobiology Goals Grant Growth Health Heart Heart Diseases Heart Hypertrophy Heart failure Hospitalization Human Hypertrophy Incidence Investigation Knock-out Knowledge Lead Leadership Mass Spectrum Analysis Measures Mediating Mentors Metabolism Modification Mus Muscle Cells Myocardial Myocardium O-GlcNAc transferase Operative Surgical Procedures Pathologic Pathway interactions Patients Persons Play Positioning Attribute Post-Translational Protein Processing Prevalence Protein Inhibition Proteins Publications Publishing Reporter Research Personnel Role Serine Signal Transduction Signaling Protein Site Stress System Techniques Testing Training Transgenic Mice Transgenic Organisms Translations Treatment Failure Ventricular Verteporfin Writing career development constriction experience heart function improved in vivo inhibitor mouse model neonatal mice novel novel therapeutics overexpression peptide O-linked N-acetylglucosamine-beta-N-acetylglucosaminidase premature prevent programs repaired research and development response sham surgery skills skills training targeted treatment transcription factor

项目摘要

Project Summary/Abstract: Every year, approximately 550,000 Americans are diagnosed with heart failure. Half of these patients die within 5 years of diagnosis. Several lines of evidence suggest that a post translational modification of proteins, O-GlcNAcylation (OGN), plays a key role in the response of the heart to stress, regulating both health and disease. I discovered chronic exposure to increased OGN causes heart failure, whereas decreased OGN can protect the heart. However, we lack detailed understanding of how OGN contributes to heart health and disease. This gap in knowledge hinders the development of O-GlcNAc-targeted therapies to prevent heart failure. OGN occurs on thousands of proteins in the heart and is regulated by only two enzymes, OGT (adds modification) and OGA (removes modification). Myocardial OGN is increased in failing hearts, but it was unknown if increased OGN was a cause of heart failure. To answer this question, I developed a novel line of transgenic mice overexpressing either OGT, or OGA, in myocardium. OGT hearts have more OGN and these mice have myocardial hypertrophy, heart failure and die prematurely from arrhythmias. In contrast, OGA animals had less OGN and were protected against cardiac stress. My new findings support a role for the Yes Associated Protein (YAP) in causing myocardial hypertrophy in response to excess OGN. The short-term goal of this proposal is to execute complementary research and career development plans to address these gaps in knowledge and position myself as a cardiac O-GlcNAc expert. The long-term goal of this proposal is to use the knowledge gained to facilitate the development of O-GlcNAc targeted therapies for heart failure. Here, I propose to test the specific hypothesis that excess OGN activates YAP and modulates adverse cardiac remodeling through enhanced transcription of pro- hypertrophic genes. The 5-year career development plan proposed here will provide me formal training in four crucial areas: (1) Advanced techniques in glycobiology; (2) advanced training in protein mass spectrometry; (3) proficiency in protein bioinformatics; (4) enhanced grant writing and leadership skills. At the conclusion of this award period, I will have acquired the skills and training necessary to become a leader in the area of cardiac O-GlcNAc biology, an under-explored area of scientific investigation that shows great promise for translation into novel therapies.

项目摘要/摘要：每年，大约有 550,000 名美国人被诊断患有心力衰竭。这些一半患者在诊断后 5 年内死亡。多条证据表明翻译后蛋白质的修饰，O-GlcNAcylation (OGN)，在心脏对心脏的反应中起着关键作用。压力，调节健康和疾病。我发现长期暴露于增加的 OGN 导致心力衰竭，而降低 OGN 可以保护心脏。但我们缺乏详细的了解 OGN 如何促进心脏健康和疾病。这种知识差距阻碍了预防心力衰竭的 O-GlcNAc 靶向疗法的开发。 OGN 发生在心脏中的数千种蛋白质上，并且仅受两种酶 OGT 的调节（添加修改）和 OGA（删除修改）。衰竭时心肌 OGN 增加但尚不清楚 OGN 增加是否是心力衰竭的原因。为了回答这个问题，我开发了一种新的转基因小鼠品系，在心肌中过度表达 OGT 或 OGA。奥格特心脏有更多 OGN，这些小鼠出现心肌肥大、心力衰竭并死亡过早地出现心律失常。相比之下，OGA 动物的 OGN 较少并且受到保护对抗心脏应激。我的新发现支持 Yes 相关蛋白 (YAP) 在过量 OGN 导致心肌肥厚。本次短期目标建议执行补充研究和职业发展计划来解决这些问题知识差距并将自己定位为心脏 O-GlcNAc 专家。本次活动的长远目标建议利用所获得的知识来促进 O-GlcNAc 靶向药物的开发心力衰竭的治疗方法。在这里，我建议检验过量 OGN 的具体假设激活 YAP 并通过增强 pro- 转录来调节不良心脏重塑肥大基因。这里提出的五年职业发展计划将为我提供四个关键方面的正式培训领域：（1）糖生物学先进技术； (2)蛋白质质量进阶训练光谱测定；（3）熟练掌握蛋白质生物信息学； (4) 加强拨款写作和领导力技能。在本奖励期结束时，我将获得必要的技能和培训成为心脏 O-GlcNAc 生物学领域的领导者，这是一个尚未充分探索的科学领域研究显示转化为新疗法的巨大前景。