Metabolic drivers and sensors of cell proliferation in pulmonary hypertension

肺动脉高压细胞增殖的代谢驱动因素和传感器

• 批准号: 9086013
• 负责人: Jarrod W. Barnes
• 金额: $ 8.98万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-15 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9086013
• 关键词: Activities of Daily Living; Acute; Animal Model; Animals; Area; Award; Basic Science; Blood Vessels; Cardiac health; Cardiopulmonary; Cell Culture Techniques; Cell Cycle; Cell Proliferation; Cell Survival; Cells; Cessation of life; Characteristics; Chicago; Chronic; Clinic; Clinical; Clinical Data; Clinical Research; Collaborations; Coupled; Cues; Data; Deterioration; Development; Disease; Disease Outcome; Enzymes; Equilibrium; Functional disorder; Glucosamine; Glucose; Glycobiology; Hemorrhage; Hexosamines; Homeostasis; Human; Hypoxia; Illinois; Laboratories; Lead; Life; Link; Lung; Metabolic; Metabolism; Mission; Modeling; Molecular; Nature; New York; O-GlcNAc transferase; Outcome; Oxidative Stress; Pathogenesis; Pathology; Pathway interactions; Patients; Personal Satisfaction; Post-Translational Protein Processing; Postdoctoral Fellow; Prevention; Process; Progressive Disease; Public Health; Publishing; Pulmonary Heart Disease; Pulmonary Hypertension; Pulmonary artery structure; Quality of life; Regulation; Reperfusion Injury; Research; Role; Sampling; Scientist; Site; Smooth Muscle Myocytes; Staging; Stress; Testing; Tissues; Training; Translational Research; Trauma; Universities; Vascular Diseases; Vascular remodeling; Work; abstracting; career; effective therapy; end stage disease; experience; glucose metabolism; human data; improved; innovation; insight; intercellular communication; metabolic profile; mouse model; novel strategies; nutrient metabolism; post-doctoral training; pre-doctoral; premature; primary pulmonary hypertension; programs; response; sensor; skills; targeted treatment; vasoconstriction

 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.

 DESCRIPTION (provided by application): 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 application took a unique opportunity to join the Cleveland Clinic Pathobiology Department for his postdoctoral training to gain experience in human translational research. K99应用程序将在基础研究方面的专业知识和他的民间转化后/临床研究结合，以创造独立的翻译职业。到2的结尾 奖项的K99年份部分，他将建立一个用于肺动脉高压的动物模型，获得了为3年R00过渡询问该模型的必要技能，并将其与他对人类临床研究的持续研究联系起来。研究计划：特发性肺动脉高压（IPAH）是一种进行性疾病，可导致心肺功能和过早死亡恶化。目前，IPAH被认为是一种血管疾病，包括葡萄糖代谢功能失调在内的代谢失调已成为该疾病病理生物学的主要研究领域。多个过程可以受IPAH中存在的代谢功能障碍的控制，包括增强的肺血管细胞增殖，血管重塑和血管收缩。这很明显需要更有效的疗法，以针对IPAH的潜在疾病过程。我们最近发表了说，O连接的N-乙酰基葡萄糖胺（O-GLCNAC）转移酶（OGT）活性显示出可增强肺动脉平滑肌细胞增殖和较差的IPAH疾病结局。 OGT是一种分子应力“传感器”，负责涉及细胞信号，细胞周期，增殖和 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轴是通过明显调节基本过程（包括细胞增殖和营养代谢）的疾病病理学的“驱动力”。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，创伤性出血和缺血/再灌注损伤的发作。该提案的中心假设是HBP通量和OGT/O-GLCNAC轴是IPAH早期进展的肺脉管系统至关重要的，而过度和持续的水平导致疾病的“终末期”。使用从人类细胞培养到动物模型的模型的组合，我们将通过研究以下特定目的来检验我们的假设：AIM 1（K99；人类临床训练和过渡）：确定机制，从而调节OGT/O-GLCNAC轴调节IPAH中的葡萄糖利用率和代谢性。 AIM 2（K99，R00）：研究IPAH的发病机理和缺氧/Sugen小鼠模型中OGT/O-GLCNAC轴的特定分子调节剂。 AIM 3（R00，独立性）：确定使用缺氧/Sugen小鼠模型在PAH早期进展中增加的OGT/O-GLCNAC轴的作用。拟议的K99/R00应用具有创新性，因为它：（i）利用教义培训，通过卓越的血糖学位（PEG）站点（克利夫兰诊所和约翰·霍普金斯大学）以及其他重要地点（纽约大学和伊利诺伊州大学 - 奇卡哥大学）之间的互动来利用教学培训； （ii）唤起人类IPAH样品和缺氧/Sogen小鼠模型的转化研究，以确定有助于OGT/O-GLCNAC轴不平衡的分子调节剂及其对IPAH中异常葡萄糖代谢和细胞增殖的影响； （iii）在PI，糖生物学领域成立的科学家以及肺血管疾病的临床医生/科学家之间建立了长期的核心合作。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发病机理和进展的低估，并为IPAH的病理学提供新的见解，以最终提高患者的功能能力，生活质量和长期生存。