Control of sphingosine-1-phosphate distribution.

1-磷酸鞘氨醇分布的控制。

基本信息

批准号：
8043269
负责人：
Susan Ruth Schwab
金额：
$ 42.25万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-12-01 至 2015-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8043269
关键词：
Active Sites Adverse effects Affect Anti-Inflammatory Agents Anti-inflammatory Autoimmune Process Bathing Binding Sites Biology Blood Blood Circulation Blood Vessels Bone Marrow Cell membrane Cells Chimera organism Cleaved cell Clinical Trials Data Drug Delivery Systems Endothelial Cells Enzymes Epithelial Cells Gatekeeping Genes Grant Homeostasis Human Immune Immune response Inflammation Inflammatory Response Lipids Lymph Lymphocyte Lymphoid Lymphoid Tissue Maps Measures Membrane Messenger RNA Metabolic Metabolism Minor Mus Organ Organ Transplantation Pattern Pharmaceutical Preparations Phenotype Phospholipids Phosphoric Monoester Hydrolases Plasma Play Positioning Attribute Postdoctoral Fellow Radiation Relative (related person)Reporting Research Resistance Role Signal Transduction Source Sphingolipids Sphingosine-1-Phosphate Receptor T-Lymphocyte Testing Thymus Gland Tissues Variant Vascular Endothelial Cell Vertebrates Yeasts angiogenesis cell type design extracellular improved interstitial lipid phosphate phosphatase prevent response sphingosine 1-phosphate sphingosine-1-phosphate lyase sphingosine-1-phosphate phosphatase tool wasting

项目摘要

DESCRIPTION (provided by applicant): The signaling lipid sphingosine-1-phosphate (S1P) plays critical roles in mammalian biology. The concentration of S1P is high in blood, and plasma S1P stabilizes junctions between vascular endothelial cells. The concentration of S1P is low in lymphoid tissues compared to blood and lymph, and S1P compartmentalization is required to maintain proper lymphocyte circulation. Although S1P in lymphoid organs is low in homeostasis, the concentration of S1P may increase upon inflammation, and increases in tissue S1P have been reported to promote angiogenesis and to enhance pro-inflammatory responses of innate and adaptive immune cells. Drugs targeting S1P signaling and S1P metabolism are currently in clinical trials as immune suppressants. By blocking lymphocyte exit from lymphoid organs, these drugs prevent activated T cells from reaching transplanted organs or organs that are subject to autoimmune attack. These drugs may also have direct anti-inflammatory effects. Despite S1P's vital functions, little is understood about how its distribution is controlled. To maintain low tissue S1P, two sources must be contained. First, tissues are constantly bathed with plasma to bring nourishment and remove waste. Plasma S1P must be prevented from entering, or removed from, the organs. Second, all cells are thought to make S1P intracellularly during the course of membrane sphingolipid metabolism. This intracellular S1P must be destroyed before it is secreted into the interstitial space. This grant investigates how S1P concentrations in the lymphoid organs are regulated. PUBLIC HEALTH RELEVANCE: Drugs targeting sphingosine-1-phosphate (S1P) receptors and S1P metabolic enzymes are in clinical trials as immune suppressants. There is an urgent need to understand how S1P distribution is controlled both to design improved therapies and to anticipate potential side-effects.

描述（由申请人提供）：信号脂质 1-磷酸鞘氨醇 (S1P) 在哺乳动物生物学中发挥着关键作用。血液中S1P的浓度很高，血浆S1P可以稳定血管内皮细胞之间的连接。与血液和淋巴相比，淋巴组织中的 S1P 浓度较低，并且需要 S1P 区室化来维持适当的淋巴细胞循环。尽管淋巴器官中的 S1P 稳态较低，但炎症时 S1P 的浓度可能会增加，并且据报道，组织中 S1P 的增加可促进血管生成并增强先天性和适应性免疫细胞的促炎反应。针对 S1P 信号传导和 S1P 代谢的药物目前正在作为免疫抑制剂进行临床试验。通过阻止淋巴细胞从淋巴器官排出，这些药物可防止活化的 T 细胞到达移植器官或遭受自身免疫攻击的器官。这些药物也可能具有直接的抗炎作用。尽管 S1P 具有重要的功能，但人们对其分布如何控制知之甚少。为了维持低组织 S1P，必须包含两个来源。首先，组织不断地沐浴在血浆中，以提供营养并清除废物。必须防止血浆 S1P 进入器官或从器官中清除。其次，所有细胞都被认为在膜鞘脂代谢过程中在细胞内产生 S1P。这种细胞内的 S1P 在分泌到细胞间隙之前必须被破坏。此项资助研究了淋巴器官中 S1P 浓度的调节方式。公共健康相关性：针对 1-磷酸鞘氨醇 (S1P) 受体和 S1P 代谢酶的药物作为免疫抑制剂正在进行临床试验。迫切需要了解如何控制 S1P 分布，以设计改进的疗法并预测潜在的副作用。