Mechanisms of metabolic dysregulation in pulmonary hypertension

肺动脉高压代谢失调的机制

• 批准号: 9126339
• 负责人: Raed A. Dweik
• 金额: $ 60.03万
• 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: 2016-04-15 至 2020-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9126339
• 关键词: Animal Disease Models; Animal Model; Animals; Area; Bacteria; Basic Science; Binding Sites; Biological Assay; Biological Availability; Blood Vessels; Calmodulin; Cardiac health; Cardiopulmonary; Cell Culture Techniques; Cell Proliferation; Cells; Cessation of life; Clinical; Clinical Markers; Clinical Research; Coupled; Data; Deterioration; Diet; Dietary Intervention; Dimerization; Disease; Disease Outcome; Dyslipidemias; Effectiveness; Embryo; Endothelial Cells; Exercise; Experimental Animal Model; Experimental Models; Functional disorder; Glucose; Glycosylated hemoglobin A; Goals; Hexosamines; High Density Lipoprotein Cholesterol; Human; Hyperglycemia; Immunoblotting; Immunoprecipitation; Insulin; Insulin Resistance; Intervention; Knock-out; Life; Link; Lung; Measures; Metabolic; Metabolic Pathway; MicroRNAs; Mission; Modeling; Modification; Molecular; Nitric Oxide; O-GlcNAc transferase; Obesity; Outcome; Pathogenesis; Pathway interactions; Patients; Personal Satisfaction; Phosphorylation; Post-Translational Protein Processing; Prevention; Process; Production; Progressive Disease; Public Health; Publishing; Pulmonary Heart Disease; Pulmonary Hypertension; Regulation; Reporting; Research; Research Personnel; Role; Severities; Structure of parenchyma of lung; System; Testing; Therapeutic Intervention; UDP-glucosamine; Work; base; design; diabetic; diet and exercise; effective therapy; exercise intervention; follow-up; gain of function; glucose metabolism; human disease; improved; insight; loss of function; metabolomics; mortality; novel; premature; primary pulmonary hypertension; programs; public health relevance; response; sugar nucleotide; targeted treatment; therapeutic target; therapy design; vasoconstriction

 DESCRIPTION (provided by applicant): Idiopathic pulmonary arterial hypertension (IPAH) is a progressive disease that leads to deterioration in cardiopulmonary function and premature death. Metabolic dysregulation has emerged as a major area of research in the pathobiology of IPAH, including the altered bioavailability of nitric oxide (NO) and dysregulated glucose metabolism. Several processes may be governed by the metabolic dysfunction present in IPAH, including enhanced pulmonary vascular cell proliferation and vasoconstriction. Our long-term goal is to understand the role of the metabolic abnormalities in IPAH pathogenesis in order to design therapeutic interventions for the disease. Our effectiveness to design therapies in IPAH will be enhanced by understanding the link between glucose dysregulation, aberrant cell proliferation, and NO deficiency in the human disease and experimental animal models. The central hypothesis of this proposal is that abnormal glucose utilization and flux through the hexosamine biosynthetic pathway (HBP) drives cell proliferation and NO deficiency in IPAH. The hypothesis has been formulated based on our already published studies and recently generated preliminary data in humans and animal models. Our rationale for the proposed research is designed to establish the effects of glucose key metabolic dysregulation in IPAH by focusing on the rate-limiting OGT/O- GlcNAc axis of the HBP. Mechanistic insights will be gained by studying the HBP in animal models of the disease. The potential of this axis as a therapeutic target in IPAH will be tested by evaluating whether the OGT/O-GlcNAc axis and disease outcomes are modifiable by diet and exercise. Thus, we will test this hypothesis by pursuing the following specific aims: AIM 1) Determine the mechanistic role of the OGT/O- GlcNAc axis in cell proliferation in IPAH and experimental animal models of the disease; AIM 2) Investigate the specific molecular regulation of eNOS activity by O-GlcNAc in IPAH pathogenesis; and AIM 3) Establish glucose metabolic dysregulation as a modifiable marker of clinical outcomes in IPAH. The proposed research is significant because it will: (i) establish glucose dysregulation, through the HBP and the OGT/O-GlcNAc axis as the driver for the abnormal pulmonary vascular cell proliferation; (ii) determine the extent to which these metabolic abnormalities correlate with IPAH severity and outcomes, and (iii) establish an exercise and diet intervention as a means of improving disease outcomes.

 描述（由申请人提供）：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，代谢失调已成为 IPAH 病理学的主要研究领域，包括生物利用度。 IPAH 中存在的代谢功能障碍可能控制一氧化氮 (NO) 和葡萄糖代谢失调，包括肺血管细胞增殖增强和葡萄糖代谢失调。我们的长期目标是了解代谢异常在 IPAH 发病机制中的作用，以便设计针对该疾病的治疗干预措施，通过了解葡萄糖失调与异常细胞增殖之间的联系，我们将提高设计 IPAH 疗法的有效性。 ，以及人类疾病和实验动物模型中的 NO 缺乏。该假设的中心假设是葡萄糖利用和通过己糖胺生物合成途径 (HBP) 的异常驱动细胞增殖和 IPAH 中的 NO 缺乏。基于我们已经发表的研究和最近在人类和动物模型中生成的初步数据，我们提出的研究的基本原理旨在通过关注限速 OGT/O-GlcNAc 轴来确定 IPAH 中葡萄糖关键代谢失调的影响。通过研究该疾病的动物模型中的 HBP，可以获得机制见解。通过评估 OGT/O-GlcNAc 轴和疾病结果是否可以通过以下方式进行修改，可以测试该轴作为 IPAH 治疗靶点的潜力。因此，我们将通过追求以下具体目标来检验这一假设： 目的 1) 确定 OGT/O-GlcNAc 轴在 IPAH 和该疾病的实验动物模型中的机制作用； O-GlcNAc 在 IPAH 发病机制中对 eNOS 活性的特异性分子调节；以及 AIM 3) 建立葡萄糖代谢失调作为 IPAH 临床结果的可改变标志。将：（i）通过 HBP 和 OGT/O-GlcNAc 轴确定葡萄糖失调作为异常肺血管细胞增殖的驱动因素；（ii）确定这些代谢异常与 IPAH 严重程度和结果的相关程度，以及(iii) 建立运动和饮食干预作为改善疾病结果的手段。