Glycoconjugates and Cardiovascular Disease

描述(由申请者提供)：这项糖科学卓越计划(PEG)由5个项目和4个核心组成，其中包括一个包含4个子核心组件的共享资源核心。我们组建了一支由领先的和后起之秀的血糖科学家组成的团队，不仅是为了阐明糖结合物在心血管疾病中的作用和缺血时的心脏保护，还为了能够创建一个世界级的讲座和实践课程，以培训专注于NHLBI使命的未来血糖科学研究的领导者。这一聚乙二醇组分还将使世界上一些最好的心脏病研究专家关注糖共轭化合物在心脏病中的作用。这一聚乙二醇组分的中心主题是细胞外和细胞内糖结合物在保护心脏或导致动脉粥样硬化和心肌病，最终导致心肌梗死和心力衰竭的机制中的作用。项目1将研究O-GlcN酰化和磷酸化在糖尿病心肌病中对心肌细胞线粒体和收缩蛋白的串扰作用。项目1将广泛利用核心C中的所有子核，并将使用核心D来评估增加的O-GlcNAc对心肌细胞生理和功能的作用。项目2将调查这一悖论，即虽然O-GlcNAc的长期增加会导致疾病，但O-GlcNAc的短期增加是心脏保护的。项目2将利用核心C的所有子核心和核心D来评估与O-GlcNAc介导的心脏保护相关的生理事件。项目3检验了一种假设，即心肌细胞和周围成纤维细胞产生的细胞表面和分泌的糖偶联物对导致最终灾难性心力衰竭和脑梗塞的微环境有贡献。糖蛋白和多糖的细胞表面和分泌体将被定义在承受氧化应激的心脏中。项目3严重依赖亚核C1，直接与项目4和5交互，并将广泛使用核心D来监测心脏和心肌细胞生理。项目4将阐明细胞表面和细胞内糖蛋白在导致缺血、心肌梗死和中风的血小板病理性激活中的作用。项目4将利用核心C的大部分，并将与项目1在血小板胞内多糖和信号转导方面进行广泛的互动。项目5将调查神经鞘糖脂在动脉粥样硬化进展中的作用，导致ML和心力衰竭。项目5将广泛使用子核C1、C3和核心D，并将直接与项目3互动。所有的项目和核心不仅将导致一个协同计划，极大地扩展我们对糖结合物在导致心脏病发作和心力衰竭的分子和细胞过程中所起作用的知识，而且它们都将协同帮助创造一个广泛而深入的培训环境，为培养未来NHLBI靶向疾病的糖结合研究领导者提供帮助。相关性：细胞外和细胞内糖结合物直接导致动脉粥样硬化、心肌梗死和心力衰竭的病因。这个聚乙二醇组带来了一组领先的糖科学专家，不仅阐明了糖共轭在这些疾病过程中的作用，而且还创建了一支有资格领导世界级培训经验的团队，以打造专注于NHLBI使命的糖科学的下一代领导者。(摘要结束)

DESCRIPTION (provided by applicant): This Program of Excellence in Glycosciences (PEG) is comprised of 5 projects and 4 Cores, including a Shared Resources Core that contains 4 sub-core components. We have assembled a team of leading and rising star glycoscientists to not only elucidate the roles of glycoconjugates in cardiovascular disease and cardioprotection during ischemia, but also to be able to create a world-class lecture and hands-on course to train future leaders in glycoscience research focused on the missions of the NHLBI. This PEG will also focus the attention of some of the world's best research cardiologists on the roles of glycoconjugates in heart disease. The central theme of this PEG is the roles of both extracellular and intracellular glycoconjugates in the mechanisms protecting the heart or leading to atherosclerosis and cardiomyopathies, culminating in myocardial infarction and heart failure. Project 1 will investigate the roles of the crosstalk between O-GlcNAcylation and phosphorylation on cardiomyocyte mitochondrial and contractile proteins in diabetic cardiomyopathy. Project 1 will make extensive use of all of the sub-cores in Core C and will use Core D to evaluate roles of increased O-GlcNAc on cardiomyocyte physiology and functions. Project 2 will investigate the paradox that while chronic increases in O-GlcNAc cause disease, short-term increases in O-GlcNAc are cardioprotective. Project 2 will make use of all of Core C's subcores and Core D to evaluate physiological events associated with O-GlcNAc- mediated cardioprotection. Project 3 examines the hypothesis that the cell surface and secreted glycoconjugates made by cardiomyocytes and surrounding fibroblasts contribute to the micro-environment leading to eventual catastrophic heart failure and infarction. The cell surface and secretome for glycoproteins and glycans will be defined in hearts subjected to oxidative stress. Project 3 relies heavily on sub-core C1, interacts directly with Projects 4 and 5, and will extensively use Core D to monitor cardiac and cardiomyocyte physiology. Project 4 will elucidate the roles of cell surface and intracellular glycoproteins in pathological activation of platelets leading to ischemia, myocardial infarction and stroke. Project 4 will make use of most of Core C and will extensively interact with Project 1 on platelet intracellular glycans and signaling. Project 5 will investigate the roles of glycosphinoglipids in the progression of athersclerosis leading to Ml and heart failure. Project 5 will extensively use sub-cores C1, C3 and Core D, and will directly interact with Project 3. Not only will all of the Projects and Cores lead to a synergistic program that will greatly expand our knowledge of the roles of glycoconjugates in the molecular and cellular processes leading to heart attacks and heart failure, but also they all will synergistically help create a broad and deep training environment for developing the future leaders of glycoconjugate research into diseases targeted by NHLBI. RELEVANCE: Extracellular and intracellular glycoconjugates contribute directly to the etiology of atherosclerosis myocardial infarction and heart failure. This PEG brings a group of leading experts in glycosciences to not only elucidate the roles of glycoconjugates in these disease processes, but also to create a team qualified to lead a world-class training experience to create the next leaders in glycosciences focused on the mission of NHLBI. (End of Abstract)