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

• 批准号: 10685543
• 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
• 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/10685543
• 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; Leadership; Longevity; Malignant Neoplasms; 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; Threonine; Training; Transgenic Mice; Transgenic Organisms; Translations; Treatment Failure; Ventricular; Verteporfin; Writing; aorta constriction; career development; 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; skill acquisition; skills; targeted treatment; transcription factor

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55万美国人被诊断出患有心力衰竭。其中一半 患者在诊断后的5年内死亡。几条证据表明，倒变后 蛋白质的修饰O-Glcnacylation（OGN）在心脏对的反应中起关键作用 压力，调节健康和疾病。我发现长期暴露于OGN增加 导致心力衰竭，而OGN减少可以保护心脏。但是，我们缺乏细节 了解OGN如何促进心脏健康和疾病。知识差距 阻碍了O-GLCNAC靶向疗法的发展，以防止心力衰竭。 OGN发生在心脏中的数千种蛋白质上，仅由两种酶调节OGT （添加修改）和OGA（删除修改）。心肌OGN失败了 心脏，但未知是否增加了OGN是心力衰竭的原因。要回答这个问题，我 在心肌中开发了一种过表达OGT或OGA的新型转基因小鼠系。 OGT 心脏有更多的OGN，这些老鼠患有心肌肥大，心力衰竭和死亡 从心律不齐过早。相反，OGA动物的OGN较少，受到保护 反对心脏压力。我的新发现支持与YES相关蛋白（YAP）的作用 导致心肌肥大响应过量的OGN。这个短期目标 建议是执行互补的研究和职业发展计划来解决这些问题 知识和定位自己是心脏O-GLCNAC专家的差距。这个长期目标 建议是利用获得的知识来促进目标的O-GLCNAC的发展 心力衰竭的疗法。在这里，我建议测试过多的OGN的具体假设 激活YAP并通过增强促值转录来调节心脏重塑 肥厚基因。 这里提出的5年职业发展计划将为我提供四个关键的正式培训 区域：（1）糖生物学的高级技术； （2）蛋白质质量的高级训练 光谱法； （3）精通蛋白质生物信息学； （4）增强赠款写作和领导力 技能。在此奖励期结束时，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，这是一个探索的科学领域 调查显示了转化为新疗法的巨大希望。