Role of Dimethylarginine Dimethylaminohydrolase (DDAH) in vascular and parenchymal lung diseases

二甲基精氨酸二甲氨基水解酶 (DDAH) 在血管和实质肺疾病中的作用

• 批准号: 161220048
• 负责人: Professor Dr. Ralph Schermuly
• 金额: --
• 依托单位: Biomedizinisches Forschungszentrum Seltersberg (BFS)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2010
• 资助国家: 德国
• 起止时间: 2009-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/161220048?language=en
• 关键词: Role; Dimethylarginine; Dimethylaminohydrolase; DDAH; vascular

The process of protein metabolism accumulates asymmetric and symmetric dimethylarginines (ADMA, SDMA), which impact the activity of nitric oxide synthases (NOS). These endogenous inhibitors undergo either renal elimination, or are degraded by the enzyme dimethylarginine dimethylaminohydrolase (DDAH). The objective of this project is to investigate the role of DDAH in the pathobiology of pulmonary vascular and parenchymal diseases. The overall hypothesis of this project is that DDAH-ADMA axis is differently regulated in different forms of pulmonary hypertension (PH), for example in pulmonary arterial hypertension (PAH) versus PH associated with lung fibrosis. While there is already some evidence that in the PAH a down-regulation of DDAH results in progression of PH and up-regulation of DDAH is observed in parenchymal fibro-proliferative disorders, the role of DDAH in the context of PH associated with lung fibrosis remains unknown. On the level of animal models, human lung samples and comprehensive in vitro approaches, we will profoundly investigate this scientific issue. We also aim to unravel a novel signaling cascade potentially responsible for beneficial therapeutic effects of cGMP elevating agents in experimental PAH. In addition, we will address DDAH regulatory mechanisms and investigate the effects of proton pump inhibitors (which are DDAH inhibitors) in experimental pulmonary fibrosis.

蛋白质代谢过程中积累不对称和对称二甲基精氨酸（ADMA，SDMA），影响一氧化氮合酶（NOS）的活性。这些内源性抑制剂通过肾脏消除，或被二甲基精氨酸二甲氨基水解酶（DDAH）降解。本项目的目的是研究DDAH在肺血管和实质疾病的病理生物学中的作用。该项目的总体假设是DDAH-ADMA轴在不同形式的肺动脉高压（PH）中受到不同的调节，例如在肺动脉高压（PAH）与肺纤维化相关的PH中。虽然已经有一些证据表明，在PAH中，DDAH的下调导致PH的进展，并且在实质纤维增生性疾病中观察到DDAH的上调，但DDAH在与肺纤维化相关的PH背景下的作用仍然未知。我们将在动物模型、人肺样本和全面的体外方法的水平上深入研究这一科学问题。我们还旨在揭示一种新的信号级联可能负责cGMP升高剂在实验性PAH中的有益治疗作用。此外，我们将讨论DDAH的调节机制，并研究质子泵抑制剂（DDAH抑制剂）在实验性肺纤维化中的作用。