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

项目摘要/摘要： 每年约有55万美国人被诊断为心力衰竭。其中的一半 患者在确诊后5年内死亡。有几行证据表明，翻译后的 蛋白质的修饰，O-GlcN酰化(OGN)，在心脏对 压力，调节健康和疾病。我发现长期接触OGN增加 会导致心力衰竭，而减少OGN可以保护心脏。然而，我们缺乏详细的 了解OGN如何有助于心脏健康和疾病。这种知识上的鸿沟 阻碍O-GlcNAc靶向疗法的发展，以预防心力衰竭。 OGN存在于心脏中的数千种蛋白质上，只受两种酶OGT的调节 (添加修改)和OGA(删除修改)。衰竭时心肌OGN增加 心脏，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系，在心肌中过表达OGT或OGA。OGT 心脏中有更多的OGN，这些小鼠有心肌肥厚、心力衰竭和死亡 过早地死于心律不齐。相比之下，OGA动物的OGN较少，并受到保护 对抗心脏应激。我的新发现支持是相关蛋白(YAP)在 过量的OGN会导致心肌肥大。这样做的短期目标是 建议执行补充性研究和职业发展计划以解决这些问题 知识上的差距，并将自己定位为心脏O-GlcNAc专家。这样做的长期目标是 建议利用所获得的知识，有针对性地促进O-GlcNAc的发展 治疗心力衰竭的方法。在这里，我建议检验一个具体的假设，即过量的OGN 通过增强前体转录激活YAP并调节不利的心脏重塑 肥大基因。 这里提出的5年职业发展计划将在四个关键方面为我提供正式培训 领域：(1)糖生物学的先进技术；(2)蛋白质质量的高级培训 光谱分析；(3)精通蛋白质生物信息学；(4)加强拨款筹划和领导能力 技能。在这个获奖期结束时，我将获得必要的技能和培训，以 成为心脏O-GlcNAc生物学领域的领导者，这是一个未被探索的科学领域 这项研究显示出转化为新疗法的巨大希望。

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.