Role of Sphingolipid pathways in the pathobiology of PAH

鞘脂通路在 PAH 病理学中的作用

• 批准号: 10219337
• 负责人: Roberto F. Machado
• 金额: $ 68.8万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-05 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10219337
• 关键词: Address; Affinity; Apoptotic; Area; Bioenergetics; Blood Vessels; Blood flow; Cell Proliferation; Cells; Ceramides; Cessation of life; Clinical; Data; Deterioration; Development; Disease; E2F transcription factors; Endothelial Cells; Epigenetic Process; Failure; Family; Functional disorder; Funding; G-Protein-Coupled Receptors; GPR12 gene; GPR3 gene; GPR6 gene; Gene Expression; Generations; Genes; Hypoxia; In Vitro; Lung; Lung diseases; Mammalian Cell; Mitochondria; Molecular; Pathogenesis; Pathway interactions; Patients; Phenotype; Physiological; Process; Proteins; Pulmonary Hypertension; Pulmonary artery structure; Role; SPHK1 enzyme; Signal Transduction; Smooth Muscle Myocytes; Sphingolipids; Sphingosine; Translations; Untranslated RNA; Vascular remodeling; Vasodilation; Ventricular; Vision; Workload; base; cellular targeting; chromatin remodeling; constriction; in vivo; lipid phosphate phosphatase; mortality; new therapeutic target; novel therapeutics; phosphoethanolamine; premature; pressure; pulmonary arterial hypertension; response; sphingosine 1-phosphate; sphingosine-1-phosphate lyase; sphingosine-1-phosphate phosphatase; vascular smooth muscle cell proliferation

ABSTRACT Pulmonary arterial hypertension (PAH), a rare, debilitating and fatal disease for which there is currently no available cure. There is compelling evidence that the Sphingosine kinase1/S1P signaling axis is a novel and therapeutic target for PAH. To facilitate the translation of current in vivo and in vitro observations on the role of S1P dependent signaling in PAH pathobiology, this proposal will explore the hypothesis that the Sphingosine kinase1/S1P signaling axis regulates physiologic, cellular and molecular pathways in PAH that result in pulmonary vascular remodeling. SA1 seeks to define the role of LncRNA Khps1 in miR-1 and SPHK1 expression and promoting pulmonary vascular remodeling. SA2 seeks to define molecular mechanisms by which LncRNA Khps1/SPHK1 regulate pulmonary artery smooth muscle cell mitochondrial dynamics. SA3 will investigate the role of SPHK1 in aberrant chromatin remodeling and gene expression in the development of pulmonary vascular remodeling.

摘要 肺动脉高压（PAH）是一种罕见的、使人衰弱的、致命的疾病，目前没有 可用的治疗。有令人信服的证据表明，鞘氨醇激酶1/S1 P信号轴是一种新的， PAH的治疗目标。以便于翻译目前在体内和体外观察的作用 在PAH病理生物学中的S1 P依赖性信号传导，该提议将探讨鞘氨醇 激酶1/S1 P信号轴调节PAH中的生理、细胞和分子途径， 肺血管重构SA 1试图确定LncRNA Khps 1在miR-1和SPHK 1表达中的作用 促进肺血管重塑。SA 2试图定义LncRNA的分子机制， Khps 1/SPHK 1调节肺动脉平滑肌细胞线粒体动力学。SA 3将调查 SPHK 1在肺血管发育中染色质重塑和基因表达异常中的作用 重塑