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(申请人提供)：葡萄糖代谢通量调节一氧化氮和病理基质在IPAH关键词：肺动脉高压，一氧化氮，O-GlcNAc，葡萄糖，透明质酸，氨基己糖特发性肺动脉高压(IPAH)是一种进展迅速，预后不良的心肺疾病。目前，IPAH被认为是一种由肺血管形态变化引起的血管病变。导致IPAH的分子基础尚未确定。此外，目前的治疗方法的有效性是有限的，因为它们不针对IPAH特征的特定进行性血管表型。代谢产物一氧化氮(NO)的生物利用度改变是该病的一个标志。伴随着NO缺乏，糖代谢紊乱在IPAH中得到了很好的描述。我们的长期目标是了解糖摄取/代谢失调和NO缺乏是如何促进IPAH的，并期望为该病设计治疗方法和预后指标。包括细胞增殖、炎症和血管重塑在内的多个过程受IPAH代谢功能失调的支配。有趣的是，在IPAH中，细胞外基质糖胺聚糖透明质酸(HA)也增加。然而，(I)糖摄取/代谢异常，(Ii)NO缺乏和(Iii)Ipah产生HA之间的主要联系尚未阐明。更重要的是，在IPAH中触发和保持这些不同表型的分子机制尚不清楚。这一建议的中心假设是，Ipah中HA的产生增加和NO缺乏是由于葡萄糖摄取增加和氨基己糖生物合成途径(HBP)的激活所致。这一假设是基于之前产生的初步数据提出的。我们提出这项研究的基本原理是确定IPAH葡萄糖代谢流量增加对NO缺乏和HA产生和功能的影响，以确定这些分子在维持IPAH原代内皮细胞和平滑肌细胞增殖、迁移和血管重塑方面所起的调节作用(S)。在强大的初步数据的指导下，这一假说将通过追求两个具体目标来检验：1)研究代谢流调节Ipah中NO缺乏、血管增殖和重塑的机制；2)确定与氨基己糖生物合成和HA产生异常相关的调节机制。这项研究具有重要意义，因为它将促进我们对HBP作为糖细胞感受器、NO产生调节器和肺病理基质促进器在IPAH中的功能作用的理解。最终，这项拟议的工作将阐明HBP在IPAH病理生物学中调节肺微环境的重要作用，并确定潜在的治疗靶点。