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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：
8861048
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/8861048
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 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 angiogenesis autocrine constriction endothelial dysfunction genetic approach in vivo inhibitor/antagonist mouse model novel novel strategies pressure public health relevance research study 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. .