Metabolic drivers and sensors of cell proliferation in pulmonary hypertension

 描述（由申请人提供）：项目摘要/摘要标题：肺动脉高压中细胞增殖的代谢驱动器和传感器关键词：肺动脉高压，葡萄糖代谢，O-GlcNAc，细胞增殖K99途径至R 00独立性：申请人利用独特的机会加入克利夫兰诊所病理生物学部门进行博士后培训，以获得人类转化研究的经验。K99应用程序将结合联合收割机他在基础研究和他的博士后翻译/临床研究博士前的专业知识，创造一个独立的，翻译的职业生涯。到2月底， 在K99年的获奖部分中，他将建立肺动脉高压的动物模型，获得必要的技能来询问该模型的3年R 00过渡，并将其与他继续研究的人类临床研究联系起来。 研究计划：特发性肺动脉高压（IPAH）是一种进行性疾病，可导致心肺功能恶化和过早死亡。目前，IPAH被认为是一种血管病，代谢失调，包括葡萄糖代谢失调，已成为该疾病病理生物学的主要研究领域。IPAH中存在的代谢功能障碍可能控制几个过程，包括增强的肺血管细胞增殖、血管重塑和血管收缩。因此，明确需要靶向IPAH中的潜在疾病过程的更有效的疗法。我们最近发表了O-连接的N-乙酰氨基葡萄糖（O-GlcNAc）转移酶（OGT）活性的增加显示出增强肺动脉平滑肌细胞增殖和恶化IPAH疾病的结果。OGT是一种分子应激“传感器”，负责参与细胞信号传导、细胞周期、增殖和细胞凋亡的蛋白质的O-GlcNAc修饰。 营养代谢OGT/O-GlcNAc轴的适当稳态是细胞活力和调节所必需的。当升高和持续时，OGT/O-GlcNAc轴通过显著调节基本过程（包括细胞增殖和营养代谢）而成为疾病病理学的“驱动者”。另一方面，OGT/O-GlcNAc轴内的即时和暂时的稳态变化可以保护细胞免受氧化应激、缺氧、创伤出血和缺血/再灌注损伤的发生。该建议的中心假设是HBP通量和OGT/O-GlcNAc轴是在IPAH的早期进展中保护肺脉管系统的基础，而过量和持续的水平导致疾病的“终末期”。使用从人细胞培养到动物模型的模型组合，我们将通过研究以下具体目标来测试我们的假设：AIM 1（K99;人临床训练和过渡）：确定OGT/O-GlcNAc轴调节IPAH中葡萄糖利用和代谢的机制。目的2（K99，R 00）：研究OGT/O-GlcNAc轴在IPAH发病机制中的特异性分子调节因子，并建立缺氧/Sugen小鼠模型。目的3（R 00，独立性）：使用缺氧/sugen小鼠模型确定OGT/O-GlcNAc轴增加在PAH早期进展中的作用。拟议的K99/R 00应用程序具有创新性，因为它：（i）通过糖科学卓越计划（PEG）站点之间的互动利用教学培训（克利夫兰诊所和约翰霍普金斯大学）以及其他重要研究中心（纽约大学和伊利诺伊大学芝加哥分校）;（ii）引起来自人IPAH样品和缺氧/sugen小鼠模型的转化研究，以确定有助于OGT/O-1失衡的分子调节剂。GlcNAc轴及其对IPAH中异常葡萄糖代谢和细胞增殖的影响;以及（iii）启动PI、糖生物学领域的知名科学家和肺血管疾病临床医生/科学家之间的长期核心合作。该项目将确定葡萄糖代谢和细胞增殖的传感器和驱动因素，改善我们对IPAH发病机制和进展的理解，并为IPAH的病理生物学提供新的见解，以最终改善患者的功能能力，生活质量和长期生存。

 DESCRIPTION (provided by applicant): Project Summary/Abstract Title: Metabolic drivers and sensors of cell proliferation in pulmonary hypertension Key Words: Pulmonary hypertension, glucose metabolism, O-GlcNAc, cell proliferation K99 pathway to R00 independence: The applicant took a unique opportunity to join the Cleveland Clinic Pathobiology Department for his postdoctoral training to gain experience in human translational research. The K99 application will combine his pre-doc expertise in basic research and his post-doc translational/clinical research to create an independent, translational career. By the end of the 2 year K99 portion of the award, he will have established an animal model for pulmonary hypertension, acquired the necessary skills to interrogate this model for the 3-year R00 transition, and link this it to his continued study of human clinical research. Research Plan: Idiopathic pulmonary arterial hypertension (IPAH) is a progressive disease that leads to deterioration in cardiopulmonary function and premature death. Presently, IPAH is considered a vasculopathy, and metabolic dysregulation, including dysregulated glucose metabolism, has emerged as a major area of research in the pathobiology of the disease. Several processes may be governed by the metabolic dysfunction present in IPAH, including enhanced pulmonary vascular cell proliferation, vascular remodeling, and vasoconstriction. Thus, there is a clear need for more effective therapies that target the underlying disease processes in IPAH. We recently published that increased O-linked N-acetyl-glucosamine (O-GlcNAc) transferase (OGT) activity was shown to enhance pulmonary arterial smooth muscle cell proliferation and worsen IPAH disease outcomes. OGT is a molecular stress `sensor' and is responsible for the O-GlcNAc modification of proteins that are involved in cell signaling, cell cycle, proliferation, and nutrient metabolism. Proper homeostasis of the OGT/O-GlcNAc axis is required for cell viability and regulation. When elevated and sustained, the OGT/O-GlcNAc axis is a `driver' of disease pathology through the marked regulation of fundamental processes, including cell proliferation and nutrient metabolism. On the other hand, instant and temporary homeostatic changes within the OGT/O-GlcNAc axis can protect cells from the onset of oxidative stress, hypoxia, trauma hemorrhage, and ischemia/reperfusion injury. The central hypothesis of this proposal is that HBP flux and the OGT/O-GlcNAc axis is fundamental to protect the lung vasculature in the early progression of IPAH, while excessive and sustained levels lead to the `end-stage' of the disease. Using a combination of models ranging from human cell culture to animal models, we will test our hypothesis by investigating the following specific aims: AIM 1 (K99; human clinical training and transition): Determine the mechanism(s) whereby the OGT/O-GlcNAc axis regulates glucose utilization and metabolism in IPAH. AIM 2 (K99, R00): Investigate the specific molecular regulator(s) of the OGT/O-GlcNAc axis in the pathogenesis of IPAH and a hypoxia/sugen mouse model. AIM 3 (R00, independence): Determine the role of the increased OGT/O-GlcNAc axis in the early progression of PAH using a hypoxia/sugen mouse model. The proposed K99/R00 application is innovative because it: (i) utilizes didactic training leveraged through the interaction between the Programs of Excellence in Glycoscience (PEG) sites (Cleveland Clinic and Johns Hopkins University) as well as other significant sites (New York University and University of Illinois-Chicago); (ii) evokes translational research from both human IPAH samples and hypoxia/sugen mouse models to determine the molecular regulators that contribute to the imbalance of the OGT/O-GlcNAc axis and its impact on aberrant glucose metabolism and cell proliferation in IPAH; and (iii) launches long-term, core collaborations between the PI, established scientists in the field of glycobiology, and clinicians/scientists in pulmonary vascular disease. The project will identify the sensors and drivers of the glucose metabolism and cell proliferation, improve our understating of IPAH pathogenesis and progression, and offer new insights into the pathobiology of IPAH to ultimately improve patient functional capacity, quality of life, and long-term survival.