Glucose Metabolic Flux Regulates NO and Pathologic Matrices in IPAH

葡萄糖代谢通量调节 IPAH 中的 NO 和病理基质

• 批准号: 8763885
• 负责人: Jarrod W. Barnes
• 金额: $ 5.48万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-12-01 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8763885
• 关键词: Acetylglucosamine; Affect; Anabolism; Arteries; Biological Availability; Blood; Blood Vessels; Cardiopulmonary; Cell Culture Techniques; Cell Proliferation; Cells; Cessation of life; Conditioned Culture Media; Data; Deterioration; Disease; Effectiveness; Endothelial Cells; Extracellular Matrix; Face; Female; Glucosamine; Glucose; Glutamine; Glycolysis; Glycosaminoglycans; Goals; Hexosamines; Human; Hyaluronan; Immunoblotting; Immunoprecipitation; Individual; Inflammation; Life; Light; Link; Lung; Measures; Metabolic; Metabolism; Mission; Modeling; Modification; Molecular; Nitric Oxide; Nutrient; Pathogenesis; Pathologic; Pathway interactions; Patients; Personal Satisfaction; Phenotype; Phosphorylation; Polymers; Positron-Emission Tomography; Prevention; Process; Production; Prognostic Marker; Progressive Disease; Public Health; Pulmonary Heart Disease; Pulmonary Hypertension; Regulation; Reporting; Research; Role; Smooth Muscle Myocytes; Structure of parenchyma of lung; Testing; Therapeutic; Tissues; Uridine Diphosphate Glucuronic Acid; Vascular Diseases; Vascular Proliferation; Vascular remodeling; Work; base; cell motility; design; expectation; fructose-6-phosphate; glucose metabolism; glucose uptake; human NOS3 protein; human tissue; hyaluronan synthase 1; migration; novel; outcome forecast; premature; public health relevance; pulmonary arterial hypertension; research study; sensor; sugar; sugar nucleotide; targeted treatment; tissue/cell culture; treatment strategy

DESCRIPTION (provided by applicant): Glucose Metabolic Flux Regulates NO And Pathologic Matrices In IPAH Key Words: Pulmonary hypertension, Nitric oxide, O-GlcNAc, Glucose, Hyaluronan, hexosamine Idiopathic Pulmonary arterial Hypertension (IPAH) is a rapidly progressive cardiopulmonary disease with poor prognosis. Presently, IPAH is considered a vasculopathy resulting from morphological changes of the lung vasculature. The molecular underpinnings that cause IPAH have not been determined. In addition, the effectiveness of the present therapies is limited because they do not target specific progressive vascular phenotypes characterized in IPAH. The altered bioavailability of the metabolite nitric oxide (NO) is a hallmark of the disease. Along with NO deficiency, dysregulated glucose metabolism is well described in IPAH. Our long-term goal is to understand how dysregulated glucose uptake/metabolism and NO deficiency promote IPAH with the expectation to design therapeutic treatments and prognostic indicators for the disease. Multiple processes are governed by dysregulated metabolic function in IPAH including cellular proliferation, inflammation, and vascular remodeling. Interestingly, there is also an increase in the extracellular matrix glycosaminoglycan hyaluronan (HA) in IPAH. However, the primary link between (i) dysregulated glucose uptake/metabolism, (ii) NO deficiency and (iii) HA production in IPAH have not been elucidated. More importantly, the molecular mechanisms that trigger and perpetuate these different phenotypes in IPAH remains unclear. The central hypothesis of this proposal is that enhanced HA production and NO deficiency in IPAH result from increased glucose uptake and activation of the hexosamine biosynthetic pathway (HBP). The hypothesis has been formulated based on previously generated preliminary data. Our rationale for the proposed research is designed to establish the effects of increased glucose metabolic flux in IPAH on NO deficiency and HA production and function in order to determine the regulatory role(s) these molecules have in perpetuating primary endothelial and smooth muscle cell proliferation, migration, and vascular remodeling in IPAH. Guided by strong preliminary data, this hypothesis will be tested by pursuing two specific aims: 1) Investigate the mechanisms whereby metabolic flux regulates NO deficiency, vascular proliferation and remodeling in IPAH; and 2) Determine the regulatory mechanisms associated with the abnormalities in hexosamine biosynthesis and HA production. The proposed research is significant, because it will advance our understanding of the functional role of the HBP as a glucose cellular sensor, regulator of NO production, and facilitator of lung pathological matrices in IPAH. Ultimately, the proposed work will shed light on the important role of the HBP in the regulation of the lung microenvironment in the pathobiology of IPAH and identify potential targets for therapy.

描述（由申请人提供）：葡萄糖代谢通量调节 IPAH 中的 NO 和病理基质 关键词：肺动脉高压、一氧化氮、O-GlcNAc、葡萄糖、透明质酸、己糖胺 特发性肺动脉高压 (IPAH) 是一种快速进展的心肺疾病，病情进展缓慢预后。目前，IPAH被认为是由肺血管系统形态变化引起的血管病变。引起 IPAH 的分子基础尚未确定。此外，目前的疗法的有效性是有限的，因为它们不针对以IPAH为特征的特定进行性血管表型。代谢物一氧化氮 (NO) 生物利用度的改变是该疾病的标志。除了 NO 缺乏之外，IPAH 还详细描述了葡萄糖代谢失调。我们的长期目标是了解葡萄糖摄取/代谢失调和 NO 缺乏如何促进 IPAH，并期望为该疾病设计治疗方法和预后指标。 IPAH 中代谢功能失调控制着多个过程，包括细胞增殖、炎症和血管重塑。有趣的是，IPAH 中细胞外基质糖胺聚糖透明质酸 (HA) 也有所增加。然而，IPAH 中 (i) 葡萄糖摄取/代谢失调、(ii) NO 缺乏和 (iii) HA 产生之间的主要联系尚未阐明。更重要的是，触发和维持 IPAH 中这些不同表型的分子机制仍不清楚。该提议的中心假设是，IPAH 中 HA 产量的增加和 NO 的缺乏是由于葡萄糖摄取增加和己糖胺生物合成途径 (HBP) 的激活所致。该假设是根据先前生成的初步数据制定的。我们拟议研究的基本原理旨在确定 IPAH 中葡萄糖代谢通量增加对 NO 缺乏和 HA 产生和功能的影响，以确定这些分子在维持原代内皮细胞和平滑肌细胞增殖中的调节作用， IPAH 中的迁移和血管重塑。在强有力的初步数据的指导下，这一假设将通过追求两个具体目标进行检验：1）研究代谢流调节 IPAH 中 NO 缺乏、血管增殖和重塑的机制； 2) 确定与己糖胺生物合成和HA生产异常相关的调节机制。这项研究意义重大，因为它将增进我们对 HBP 作为葡萄糖细胞传感器、NO 产生调节剂和 IPAH 中肺部病理基质促进剂的功能作用的理解。最终，拟议的工作将阐明 HBP 在 IPAH 病理学中肺微环境调节中的重要作用，并确定潜在的治疗靶点。