Endothelial sphingolipid synthesis and tissue inflammatory response

 描述(由申请人提供)：这项提案的总体目标是探索以内皮细胞为靶点的新方法，以影响包括心力衰竭在内的心血管疾病的发病机制中的血管功能。尽管有多种证据表明鞘磷脂信号的改变与血管内皮细胞功能障碍有关，但具体的分子机制尚不清楚。为此，我们将研究内皮源性鞘脂是如何调节的，以及它们在影响心力衰竭(HF)发病机制的血管功能中所起的作用。这些都是适用于所有心血管疾病的基本问题，其中内皮功能的改变是这些病理发生的关键事件。该项目将集中于我们最近的发现，即内皮鞘磷脂的合成受到内质网的一种膜蛋白Nogo-B的负调控。我们的发现证明了局部内皮鞘脂脂的产生在调节心肌炎症中的血管屏障功能中起着关键作用，并揭示了Nogo-B对内皮鞘脂合成的一种新的调节。因此，我们假设Nogo-B控制局部鞘脂的产生，从而在压力超负荷时影响内皮功能和心力衰竭。作为这一假设的推论，我们预测调节鞘磷脂合成将保护心脏免受炎症和衰竭的影响。为了验证这一假说，我们提出了以下三个具体目标：1)确定Nogo-B调节EC神经鞘脂从头合成的分子机制。2)通过在EC中条件性缺失Nogo-B，探讨内皮特异性Nogo-B在心衰发病机制中的作用。3)破译S1P作为内皮Nogo-B功能的关键效应器在EC缺乏鞘氨醇激酶1和Nogo-B的小鼠中对HF的影响的重要性。总之，这些研究将确定Nogo-B对内皮鞘脂合成的一种新的调节机制，以及它在心力衰竭发病机制中的重要性。最后，这些拟议研究的结果可能为治疗心力衰竭的新方法提供基础，在心力衰竭的治疗中，血管功能障碍和炎症导致或加剧这种病理状态。。

 DESCRIPTION (provided by applicant): The overall goal of this proposal is to explore novel ways of targeting endothelial cells to impact vascular functions in the pathogenesis of cardiovascular diseases, including heart failure. Despite a variety of evidences have linked the alteration of sphingolipid signaling to endothelial dysfunction, critical event in the development f cardiovascular pathologies, specific molecular mechanisms are poorly understood. Towards this goal, we will investigate how endothelial-derived sphingolipids are regulated and what are their roles on the vascular functions to impact the pathogenesis of heart failure (HF). These are fundamental problems that apply to all cardiovascular diseases, where the alteration of endothelial function is a critical event in the onset of these pathologies. The project will focus n our recent discovery that endothelial sphingolipid synthesis is negatively regulated by Nogo-B, a membrane protein of the endoplasmic reticulum. Our findings evidence a critical role of local endothelial sphingolipid production to regulate vascular barrier functions in myocardial inflammation and reveal a novel regulation of endothelial sphingolipid synthesis by Nogo-B. Thus, we hypothesize that Nogo-B governs the production of local sphingolipids to impact endothelial functions and heart failure during pressure overload. As corollary to this hypothesis, we predict that modulating sphingolipid synthesis will protect the heart from inflammation and failure. To test this hypothesis we are proposing the following three specific aims: 1) To define the molecular mechanisms whereby Nogo-B regulates sphingolipid de novo synthesis in EC. 2) To examine the role of endothelial specific Nogo-B on the pathogenesis of HF by conditional deletion of Nogo-B in EC. 3) To decipher the importance of S1P as a key effector of endothelial Nogo-B functions to impact HF, in mice lacking sphingosine kinase 1 and Nogo-B specifically in EC. Collectively, these studies will define a novel regulatory mechanism of endothelial sphingolipid synthesis by Nogo-B, and its importance in the pathogenesis of heart failure. Finally, the results of these proposed investigations may provide the foundation for novel approaches towards the treatment of heart failure, in which vascular dysfunction and inflammation leads to or exacerbates this pathological state. .