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.

 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因素和传感器 关键词： 肺动脉高压、葡萄糖代谢、O-GlcNAc、细胞增殖 K99 途径实现 R00 独立：申请人抓住了一个独特的机会加入克利夫兰诊所病理生物学系接受博士后培训，以获得人类转化研究的经验。K99 申请将结合他在基础研究方面的博士前专业知识和博士后的专业知识。转化/临床研究，以创建独立的转化职业 2 年底。 在 K99 年奖金的一部分中，他将建立肺动脉高压动物模型，获得必要的技能来检验该模型的 3 年 R00 过渡，并将其与他继续进行的人类临床研究计划联系起来：特发性肺动脉高压（IPAH）是一种进行性疾病，会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变，并且代谢失调（包括葡萄糖代谢失调）已成为可能。该疾病病理学的一个主要研究领域是 IPAH 中存在的代谢功能障碍，包括增强的肺血管细胞增殖、血管重塑和血管收缩，因此显然需要更有效的治疗方法。我们最近发表了针对 IPAH 潜在疾病过程的疗法，表明增加 O-连接 N-乙酰氨基葡萄糖 (O-GlcNAc) 转移酶 (OGT) 活性可增强肺动脉平滑肌细胞增殖和OGT 是一种分子应激“传感器”，负责对参与细胞信号传导、细胞周期、增殖和生长的蛋白质进行 O-GlcNAc 修饰。 OGT/O-GlcNAc 轴的适当稳态是细胞活力和调节所必需的，当 OGT/O-GlcNAc 轴升高并持续时，它通过对基本过程的显着调节，成为疾病病理学的“驱动力”。另一方面，OGT/O-GlcNAc 轴内即时和暂时的稳态变化可以保护细胞免受氧化应激、缺氧、创伤的影响。该提议的中心假设是，HBP 流量和 OGT/O-GlcNAc 轴对于 IPAH 早期进展中保护肺血管系统至关重要，而过高和持续的水平会导致“结束”。我们将使用从人类细胞培养到动物模型的组合模型，通过研究以下具体目标来检验我们的假设：AIM 1（K99；人类临床训练和过渡）：确定 OGT/O-GlcNAc 轴调节 IPAH 中葡萄糖利用和代谢的机制（K99、R00）：研究 OGT/O-GlcNAc 轴在 IPAH 发病机制中的特定分子调节剂。 IPAH 和缺氧/sugen 小鼠模型（R00，独立）：确定 OGT/O-GlcNAc 轴增加在早期进展中的作用。所提出的 K99/R00 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（克利夫兰诊所和约翰霍普金斯大学）之间的互动进行教学培训。以及其他重要网站（纽约大学和伊利诺伊大学芝加哥分校）；（ii）从人类 IPAH 样本和缺氧/sugen 小鼠模型中进行转化研究，以确定分子调节剂导致 IPAH 中 OGT/O-GlcNAc 轴的不平衡及其对异常葡萄糖代谢和细胞增殖的影响；以及 (iii) 在 PI、糖生物学领域的知名科学家和叛军之间开展长期核心合作； /肺血管疾病领域的科学家。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，提高我们对 IPAH 发病机制和进展的理解，并为 IPAH 的病理学提供新的见解，以最终改善 IPAH 的发病机制。患者的功能能力、生活质量和长期生存。