Glycoconjugates and Cardiovascular Disease

糖复合物与心血管疾病

• 批准号: 8072358
• 负责人: GERALD Warren HART
• 金额: $ 243.63万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8072358
• 关键词: Glycoconjugates; Cardiovascular; Disease

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)

描述（由申请人提供）：该糖科学卓越计划 (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和后起之秀的糖科学家组成的团队，不仅要阐明复合糖在心血管疾病和缺血期间心脏保护中的作用，而且能够创建世界一流的讲座和实践课程，以培训专注于 NHLBI 使命的糖科学研究的未来领导者。该 PEG 还将引起世界上一些最优秀的研究心脏病专家对糖复合物在心脏病中的作用的关注。该 PEG 的中心主题是细胞外和细胞内糖复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对糖尿病心肌病中心肌细胞线粒体和收缩蛋白的作用。项目 1 将广泛使用核心 C 中的所有子核心，并将使用核心 D 来评估增加的 O-GlcNAc 对心肌细胞生理学和功能的作用。项目 2 将研究这样一个悖论：虽然 O-GlcNAc 的慢性增加会导致疾病，但 O-GlcNAc 的短期增加却具有心脏保护作用。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 检验了这样的假设：心肌细胞和周围成纤维细胞产生的细胞表面和分泌的糖复合物有助于形成最终导致灾难性心力衰竭和梗塞的微环境。将在遭受氧化应激的心脏中定义糖蛋白和聚糖的细胞表面和分泌组。项目 3 严重依赖子核心 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学。项目4将阐明细胞表面和细胞内糖蛋白在导致缺血、心肌梗塞和中风的血小板病理激活中的作用。项目 4 将利用大部分核心 C，并将与项目 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将研究糖脂在导致MI和心力衰竭的动脉粥样硬化进展中的作用。项目 5 将广泛使用子核心 C1、C3 和核心 D，并将直接与项目 3 互动。所有项目和核心不仅将导致一个协同计划，将大大扩展我们对糖复合物在导致心脏病和心力衰竭的分子和细胞过程中的作用的了解，而且它们都将协同帮助创建一个广泛而深入的培训环境，以培养糖复合物研究的未来领导者 NHLBI 所针对的疾病。相关性：细胞外和细胞内糖复合物直接导致动脉粥样硬化、心肌梗死和心力衰竭的病因。该 PEG 汇集了糖科学领域的顶尖专家，不仅阐明糖复合物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，以培养专注于 NHLBI 使命的糖科学领域的下一个领导者。 （摘要完）