Glucose Metabolic Flux Regulates NO and Pathologic Matrices in IPAH

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，羟乙氨基葡萄糖，氨基己糖特发性肺动脉高压（IPAH）是一种快速进展的心肺疾病，预后不良。目前，IPAH被认为是由肺血管系统的形态学变化引起的血管病变。导致IPAH的分子基础尚未确定。此外，目前疗法的有效性是有限的，因为它们不靶向IPAH中表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疾病的标志。沿着NO缺乏，葡萄糖代谢失调在IPAH中有很好的描述。我们的长期目标是了解葡萄糖摄取/代谢失调和NO缺乏是如何促进IPAH的，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，在IPAH中触发和维持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产生的增强和NO缺乏是由于葡萄糖摄取的增加和己糖胺生物合成途径（HBP）的激活。该假设是根据先前生成的初步数据制定的。我们提出的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IPAH中维持原发性内皮和平滑肌细胞增殖、迁移和血管重塑中的调节作用。在强有力的初步数据的指导下，该假设将通过追求两个特定目标进行测试：1）研究代谢通量调节IPAH中NO缺乏、血管增殖和重塑的机制;和2）确定与己糖胺生物合成和HA产生异常相关的调节机制。这项研究意义重大，因为它将促进我们对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。

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.