Role of Sphingolipid Pathways in the Pathobiology of PAH

 描述(申请人提供)：肺动脉高压(PAH)，一种罕见的、衰弱的和致命的疾病，目前还没有可用的治疗方法。在肺部疾病的病理生物学中，有令人信服的证据表明鞘磷脂代谢物，如神经酰胺和鞘氨醇-1-磷酸(S1P)。为了促进体内和体内电流的翻译 SphK1/S1P/S1PR2在PAH病理生物学中作用的体外观察本研究将探讨SphK1/S1P/S1PR2信号轴调节PAH的生理、细胞和分子通路从而导致肺血管重塑的假说。SA1将确定SphK1在动物和血管细胞培养模型中调节高血压反应的分子机制。SA2将确定S1P信号通过S1PR2在动物和血管细胞模型中调节肺动脉高压中的作用。SA3将进行关联研究，将S1P生物合成/信号通路基因中的SNP与PAH的易感性联系起来。SA4将评估SK1和S1PR2拮抗作为治疗PAH的潜在策略。这项建议的最终目标是为开发治疗PAH的新靶点奠定基础。

 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.