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: 9055416
• 负责人: Roberto F. Machado
• 金额: $ 46.97万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 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 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9055416
• 关键词: Address; Anabolism; Animal Model; Animals; Area; Blood Vessels; Blood flow; Cell Culture Techniques; Cell Proliferation; Cell model; Ceramides; Cessation of life; Clinical; Data; Deterioration; Development; Disease; Endothelial Cells; Failure; Foundations; Functional disorder; Generations; Genes; Genetic; Goals; Health; Human Pathology; Hypoxia; In Vitro; Individual; Ligation; Link; Lung; Lung diseases; Mammalian Cell; Modeling; Molecular; Neoplasm Metastasis; Pathway interactions; Patients; Physiological; Predisposition; Process; Pulmonary Hypertension; Pulmonary artery structure; Rodent; Role; SPHK1 enzyme; Sepsis; Signal Transduction; Signaling Protein; Smooth Muscle Myocytes; Sphingolipids; Sphingosine; Testing; Therapeutic; Transcriptional Regulation; Translations; Variant; Vascular remodeling; Vasodilation; Ventricular; Vision; Workload; angiogenesis; cellular targeting; constriction; in vivo; interest; lipid mediator; lipid phosphate phosphatase; lung injury; mortality; new therapeutic target; phosphoethanolamine; premature; pressure; primary pulmonary hypertension; pulmonary arterial hypertension; response; sphingosine 1-phosphate; sphingosine-1-phosphate lyase; sphingosine-1-phosphate phosphatase; tumor progression; vascular smooth muscle cell proliferation

 DESCRIPTION (provided by applicant): Pulmonary arterial hypertension (PAH), a rare, debilitating and fatal disease for which there is currently no available cure. There is compelling evidence for sphingolipid metabolites such as ceramides and sphingosine- 1-phosphate (S1P) in the pathobiology of pulmonary disorders. To facilitate the translation of current in vivo and in vitro observations on the role of SphK1/S1P/S1PR2 in PAH pathobiology this proposal will explore the hypothesis that the SphK1/S1P/S1PR2 signaling axis regulates physiologic, cellular and molecular pathways in PAH that result in pulmonary vascular remodeling. SA1 will define molecular mechanisms by which SphK1 regulates the hypertensive response in animal and smooth muscle cell culture models. SA2 will define the role of S1P signaling via S1PR2 in regulating pulmonary hypertension in animal and smooth muscle cell models. SA3 will conduct association studies to link SNPs within S1P biosynthetic/signaling pathway genes with susceptibility to PAH. SA4 will evaluate SK1 and S1PR2 antagonism as potential therapeutic strategies in PAH. The ultimate goal of this proposal is to lay the foundation for the development of novel therapeutic targets for PAH.

 描述（由申请人提供）：肺动脉高压（PAH），一种罕见的、使人衰弱的致死性疾病，目前尚无治愈方法。有令人信服的证据表明，鞘脂代谢物，如神经酰胺和鞘氨醇-1-磷酸（S1 P）在肺部疾病的病理生物学。为了促进电流在体内和体内的转化， SphK 1/S1 P/S1 PR 2在PAH病理生物学中作用的体外观察本研究将探讨SphK 1/S1 P/S1 PR 2信号轴调节PAH中导致肺血管重构的生理、细胞和分子途径的假说。SA 1将定义SphK 1在动物和平滑肌细胞培养模型中调节高血压反应的分子机制。SA 2将确定通过S1 PR 2的S1 P信号传导在动物和平滑肌细胞模型中调节肺动脉高压中的作用。SA 3将进行关联研究，以将S1 P生物合成/信号通路基因内的SNP与PAH易感性联系起来。SA 4将评价SK 1和S1 PR 2拮抗作用作为PAH的潜在治疗策略。该提案的最终目标是为PAH的新治疗靶点的开发奠定基础。