Endothelial sphingolipid synthesis and tissue inflammatory response

内皮鞘脂合成与组织炎症反应

• 批准号: 9033144
• 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
• 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/9033144
• 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; Health; Heart; Heart Hypertrophy; Heart failure; Inflammation; Inflammatory; Inflammatory Response; Investigation; Knockout Mice; Lead; Link; Membrane Proteins; Modeling; Molecular; Mus; Myocardial; Myocardial dysfunction; Pathogenesis; Pathology; Pathway interactions; Pharmacological Treatment; Prevention; Process; Production; Public Health; Regulation; Resistance; Role; SPHK1 enzyme; Signal Transduction; Smooth Muscle Myocytes; Sphingolipids; Structure; Testing; Therapeutic; Tissues; Up-Regulation; Vascular Diseases; Vascular Smooth Muscle; angiogenesis; autocrine; constriction; endothelial dysfunction; genetic approach; in vivo; inhibitor/antagonist; mouse model; novel; novel strategies; pressure; research study; sensor; serine palmitoyltransferase; sphingosine 1-phosphate; sphingosine kinase; thermozymocidin; vascular inflammation

 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（由申请人提供）：本提案的总体目标是探索靶向内皮细胞的新方法，以影响心血管疾病（包括心力衰竭）发病机制中的血管功能。尽管有多种证据表明鞘脂信号通路的改变与内皮功能障碍有关，但其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的发病中的关键事件。该项目将集中在我们最近的发现，即内皮鞘脂的合成是负调控的Nogo-B，内质网的膜蛋白。我们的研究结果证明了局部内皮鞘脂产生在心肌炎症中调节血管屏障功能的关键作用，并揭示了Nogo-B对内皮鞘脂合成的新调节。因此，我们假设Nogo-B控制局部鞘脂的产生，从而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衰竭的影响。为了验证这一假设，我们提出了以下三个具体目标：1）确定Nogo-B调节EC中鞘脂从头合成的分子机制。 2)通过EC中Nogo-B的条件性缺失来检测内皮特异性Nogo-B在HF发病机制中的作用。 3)在EC中缺乏鞘氨醇激酶1和Nogo-B的小鼠中，解读S1 P作为内皮Nogo-B功能影响HF的关键效应物的重要性。总的来说，这些研究将确定一种新的调节机制，内皮鞘脂合成的Nogo-B，其重要性，在心力衰竭的发病机制。最后，这些研究的结果可能为治疗心力衰竭的新方法提供基础，其中血管功能障碍和炎症导致或加剧了这种病理状态。.