Mechanisms of metabolic dysregulation in pulmonary hypertension

 描述（申请人提供）：特发性肺动脉高压（IPAH）是一种导致心肺功能恶化和过早死亡的进行性疾病。代谢失调已成为IPAH病理生物学研究的一个主要领域，包括一氧化氮（NO）生物利用度的改变和葡萄糖代谢失调。IPAH中存在的代谢功能障碍可能控制几个过程，包括增强的肺血管细胞增殖和血管收缩。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。通过了解人类疾病和实验动物模型中葡萄糖调节异常、异常细胞增殖和NO缺乏之间的联系，我们设计IPAH治疗方法的有效性将得到增强。该建议的中心假设是，通过己糖胺生物合成途径（HBP）的异常葡萄糖利用和流量驱动IPAH中的细胞增殖和NO缺乏。该假设是基于我们已经发表的研究和最近在人类和动物模型中产生的初步数据而制定的。我们提出的研究的基本原理旨在通过关注HBP的限速OGT/O-GlcNAc轴来确定IPAH中葡萄糖关键代谢失调的影响。通过在疾病的动物模型中研究HBP，将获得机制上的见解。将通过评价OGT/O-GlcNAc轴和疾病结局是否可通过饮食和运动改变来测试该轴作为IPAH治疗靶点的潜力。因此，我们将通过追求以下具体目标来测试该假设：AIM 1）确定OGT/O-GlcNAc轴在IPAH和该疾病的实验动物模型中的细胞增殖中的机制作用; AIM 2）研究在IPAH发病机制中O-GlcNAc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中临床结果的可改变标志物。所提出的研究是重要的，因为它将：（i）通过HBP和OGT/O-GlcNAc轴建立葡萄糖调节异常，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严重程度和结果相关的程度，以及（iii）建立运动和饮食干预作为改善疾病结果的手段。

 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.