Glycoconjugates and Cardiovascular Disease

描述（由申请人提供）：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。我们已经组建了一个领先的和正在崛起的糖科学家团队，不仅阐明糖缀合物在心血管疾病和缺血期间的心脏保护中的作用，而且能够创建一个世界级的讲座和实践课程，以培养未来的糖科学研究领导者，专注于NHLBI的使命。这次聚乙二醇会议还将吸引一些世界上最好的研究心脏病的专家关注糖缀合物在心脏病中的作用。该PEG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 - glcnac酰化和磷酸化之间的串扰在糖尿病心肌病中对心肌细胞线粒体和收缩蛋白的作用。项目1将广泛使用Core C中的所有子核心，并将使用Core D来评估O-GlcNAc升高对心肌细胞生理和功能的作用。项目2将研究O-GlcNAc的长期升高导致疾病，而短期升高的O-GlcNAc对心脏有保护作用的悖论。项目2将利用Core C的所有亚核心和Core D来评估与O-GlcNAc介导的心脏保护相关的生理事件。项目3检验了细胞表面和由心肌细胞和周围成纤维细胞产生的分泌糖缀合物有助于导致最终灾难性心力衰竭和梗死的微环境的假设。细胞表面和糖蛋白和聚糖分泌组将在心脏受到氧化应激的定义。项目3主要依赖子核心C1，与项目4和项目5直接交互，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血小板病理活化导致缺血、心肌梗死和脑卒中中的作用。Project 4将利用大部分Core C，并与Project 1在血小板胞内聚糖和信号传导方面广泛相互作用。项目5将研究糖鞘脂在动脉粥样硬化导致Ml和心力衰竭的进展中的作用。项目5将广泛使用子核C1、C3和D，并将直接与项目3交互。所有的项目和核心不仅会导致一个协同计划，这将极大地扩展我们对糖缀合物在导致心脏病发作和心力衰竭的分子和细胞过程中的作用的认识，而且它们都将协同帮助创造一个广泛而深入的培训环境，以培养糖缀合物研究的未来领导者，研究NHLBI针对的疾病。相关性：细胞外和细胞内糖结合直接导致动脉粥样硬化性心肌梗死和心力衰竭。这一PEG带来了一群糖科学领域的领先专家，不仅阐明了糖缀合物在这些疾病过程中的作用，而且还创建了一个有资格领导世界级培训经验的团队，以培养专注于NHLBI使命的糖科学领域的下一代领导者。（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)