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

项目概要/摘要： 每年，大约有55万美国人被诊断患有心力衰竭。其中一半 患者在确诊后5年内死亡。几条证据表明翻译后 蛋白质的修饰，O-GlcNAc酰化（OGN），在心脏对 压力，调节健康和疾病。我发现长期暴露于OGN 导致心力衰竭，而降低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。这种知识上的差距 阻碍了O-GlcNAc靶向治疗的发展，以预防心力衰竭。 OGN发生在心脏中的数千种蛋白质上，仅受两种酶的调节， (adds OGA（删除修改）。衰竭时心肌OGN增加 但不知道OGN增加是否是心力衰竭的原因。为了回答这个问题，我 开发了一种新的在心肌中过表达OGT或OGA的转基因小鼠品系。OGT 心脏有更多的OGN，这些小鼠有心肌肥大，心力衰竭和死亡 过早的心律失常相比之下，OGA动物的OGN较少，并且受到保护 对抗心脏压力我的新发现支持了Yes Associated Protein（雅普）在 导致心肌肥大。短期目标是 建议是执行补充研究和职业发展计划，以解决这些问题 知识的空白，并将自己定位为心脏O-GlcNAc专家。长期目标是 建议是利用所获得的知识，以促进目标O-GlcNAc的发展 治疗心力衰竭的方法在这里，我建议测试的具体假设，过量OGN 激活雅普，并通过增强前- 肥大基因 这里提出的5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）糖生物学的高级技术;（2）蛋白质质量的高级培训 光谱学;（3）熟练掌握蛋白质生物信息学;（4）提高了赠款写作和领导能力 skills.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，这是一个尚未开发的科学领域。 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.