Fatty acid-binding proteins sustain endothelial glycolysis and arterial programming in pulmonary arterial hypertension

脂肪酸结合蛋白维持肺动脉高压中的内皮糖酵解和动脉规划

• 批准号: 10657101
• 负责人: Zhiyu Dai
• 金额: $ 57.58万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-15 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10657101
• 关键词: Animal Model; Blood Vessels; Cessation of life; Endothelium; Failure; Functional disorder; Glycolysis; Heart Hypertrophy; Lesion; Link; Molecular; Pathogenesis; Patients; Pulmonary Vascular Resistance; Reporting; Role; SOX17 gene; Signal Transduction; Transgenic Animals; Vascular remodeling; effective therapy; fatty acid metabolism; fatty acid-binding proteins; novel; novel therapeutic intervention; premature; pulmonary arterial hypertension; pulmonary vascular remodeling

Title: Fatty acid-binding proteins sustain endothelial glycolysis and arterial programming in pulmonary arterial hypertension Project Summary Pulmonary arterial hypertension (PAH) is characterized by a progressive increase of pulmonary vascular resistance and obliterative pulmonary vascular remodeling that result in right heart hypertrophy, failure, and premature death. The underlying mechanisms of vascular remodeling and obliterative vascular lesion formation remain unclear. Fatty acid metabolism dysfunction is linked to PAH. However, the mechanistic role of fatty acid metabolism in regulating pulmonary vascular remodeling in the pathogenesis of PAH has not been reported. We hypothesize that endothelial fatty acid-binding proteins 4 and 5 (FABP4-5) regulate endothelial glycolysis and arterial programming through HIF-2a/SOX17 signaling which contributes to severe vascular remodeling in the pathogenesis of PAH. We will 1) define the novel role of endothelial FABP4-5 in the pathogenesis of PAH using multiple transgenic animal models. 2) delineate the cellular and molecular mechanisms that FABP4-5 induces arterial programming and pathogenesis of PAH. Completing our proposed study will provide a novel therapeutic strategy for the effective treatment of PAH in patients.

脂肪酸结合蛋白支持血管内皮细胞糖酵解和动脉编程 肺动脉高压 项目摘要 肺动脉高压(PAH)的特征是肺组织进行性增加。 血管阻力和闭塞性肺血管重塑导致右心肥厚， 失败和过早死亡。血管重塑和闭塞的潜在机制 血管病变的形成仍不清楚。脂肪酸代谢障碍与PAH有关。然而， 脂肪酸代谢在大鼠肺血管重构调节中的作用 PAH的发病机制尚未见报道。我们假设内皮脂肪酸结合蛋白 4和5(FABP4-5)通过HIF-2a/SOX17调节内皮糖酵解和动脉编程 在PAH发病机制中参与严重血管重塑的信号转导。我们将1)定义 利用多转基因动物研究血管内皮细胞FABP4-5在PAH发病中的新作用 模特们。2)阐明FABP4-5诱导动脉编程的细胞和分子机制 以及PAH的发病机制。完成我们提议的研究将提供一种新的治疗策略 PAH患者的有效治疗。