Endothelial sphingolipid synthesis and tissue inflammatory response

内皮鞘脂合成与组织炎症反应

基本信息

批准号：
9207114
负责人：
Annarita Di Lorenzo
金额：
$ 42.38万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-03-11 至 2019-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9207114
关键词：
Anabolism Anti-Inflammatory Agents Anti-inflammatory Binding Biological Blood Blood Vessels Cardiovascular Diseases Cardiovascular Pathology Cardiovascular system Cell physiology Cells Data Development Endoplasmic Reticulum Endothelial Cells Enzymes Event Failure Fibrosis Foundations G-Protein-Coupled Receptors Goals Heart Heart Hypertrophy Heart failure Inflammation Inflammatory Inflammatory Response Investigation Knockout Mice Lead Link Membrane Proteins Modeling Molecular Mus Muscle Cells Myocardial Myocardial dysfunction Pathogenesis Pathologic Pathology Pathway interactions Pharmacological Treatment Pharmacology Prevention Process Production Public Health Regulation Resistance Role SPHK1 enzyme Signal Transduction Sphingolipids Structure Testing Therapeutic Tissues Up-Regulation Vascular Diseases Vascular Smooth Muscle angiogenesis autocrine constriction endothelial dysfunction experimental study genetic approach in vivo inhibitor/antagonist mouse model novel novel strategies pressure public health relevance sensor serine palmitoyltransferase sphingosine 1-phosphate sphingosine kinase thermozymocidin vascular inflammation

项目摘要

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. .

描述（由适用提供）：该提案的总体目标是探索靶向内皮细胞以影响心血管疾病发病机理（包括心力衰竭）的血管功能的新颖方法。尽管有多种证据将鞘脂信号传导的改变与内皮功能障碍联系在一起，但发育f心血管病理的关键事件，但对特定的分子机制的了解很少。为了实现这一目标，我们将研究如何调节内皮衍生的鞘脂，以及它们在血管功能上的作用是什么影响心力衰竭发病机理（HF）。这些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作的关键事件。该项目将集中于我们最近发现的，即内皮鞘脂合成受内质网的膜蛋白Nogo-B负调节。我们的发现证明，局部内皮鞘脂产生的关键作用是调节心肌炎症中的血管屏障功能，并揭示了Nogo-B对内皮鞘脂合成的新调节。这就是我们假设Nogo-B控制着局部鞘脂的产生，以影响压力超负荷期间的内皮功能和心力衰竭。作为这一假设的推论，我们预测调节鞘脂合成将保护心脏免受炎症和失败的影响。为了检验这一假设，我们提出以下三个特定目的：1）定义分子机制，从而调节EC中的鞘脂从头合成。 2）检查内皮特异性nogo-b在EC中Nogo-B的条件缺失中的作用。 3）破译S1P作为内皮NOGO-B功能对HF的关键作用的重要性，在缺乏鞘氨醇激酶1和EC中的Nogo-B的小鼠中。总的来说，这些研究将定义一种新型的调节机制，即通过Nogo-B进行内皮鞘脂合成，及其在心力衰竭发病机理中的重要性。最后，这些提出的研究的结果可能为治疗心力衰竭的新方法奠定了基础，其中血管功能障碍和注射导致或加剧了这种病理状态。