Molecular Pharmacology of Sphingosine 1-Phosphate

1-磷酸鞘氨醇的分子药理学

基本信息

批准号：
8309078
负责人：
KEVIN R. LYNCH
金额：
$ 35.71万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-01-01 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8309078
关键词：
Acute Address Adverse event Affect Agonist Alcohols Analytical Chemistry Biology Blood Blood Circulation Blood Vessels Blood capillaries Bradycardia Capillary Permeability Cardiovascular system Cells Chemicals Chronic Clinical Depressed mood Development Digit structure Erythrocytes Extravasation Fc Receptor Functional disorder Heart Heart Rate Human Immune system Infusion procedures Investigational Drugs Knowledge Laboratories Learning Lipids Lymphocyte Lymphopenia Maintenance Mammals Metabolic Metabolism Molecular Molecular Biology Multiple Sclerosis Mus Mutant Strains Mice Normal Range Pathology Pharmaceutical Preparations Pharmacology Phosphoric Monoester Hydrolases Physiology Plasma Positioning Attribute Prodrugs Property Rattus Research Rodent Role Route Sampling Signal Transduction Sphingolipids Sphingosine-1-Phosphate Receptor Testing Therapeutic Therapeutic Agents Time Whole Blood capillary design edg-1 Protein experience in vivo inhibitor/antagonist inorganic phosphate insight interest lymph nodes mimetics novel receptor small molecule sphingosine 1-phosphate success therapeutic development therapeutic target tool trafficking

项目摘要

DESCRIPTION (provided by applicant): Sphingosine 1-phosphate (S1P) is a bioactive lipid that circulates at triple digit nanomolar levels in plasma and at single digit micromolar levels in whole blood due to S1P's storage in erythrocytes. Circulating S1P is implicated in tonic control of lymphocyte trafficking, maintenance of endothelial integrity and control of heart rate. Blood S1P is degraded on a time scale of minutes. However, we know neither the mechanism(s) whereby S1P is cleared from circulation nor how it is transported from cells to plasma. The interest in developing therapeutics that block S1P synthesis or action add urgency to developing an understanding of how circulating S1P levels are regulated and the acute and chronic consequences of lowering circulating S1P tone. During the past period of support, we discovered new small molecule S1P receptor agonists, antagonists and synthesis inhibitors and we developed mice genetically altered for S1P signaling and metabolism. Further, we added sophisticated analytical chemistry capabilities that enable quantification of sphingolipid species in small samples. Now we propose to build on this success by using our chemical and molecular biology tools to understand S1P biology more deeply. Specifically, we will: (Aim 1) determine the range of circulating S1P levels, test the hypotheses that the lipid phosphatase LPP1 is responsible for plasma S1P degradation and that Spns2 transports S1P and (Aim 2) use S1P synthesis inhibitors to lower circulating S1P acutely and chronically and determine the effects on lymphocyte trafficking, capillary permeability and heart rate. Our extensive experience in S1P chemical biology, as evidenced by our success in discovering S1P receptor agonist and antagonists with drug-like properties, enables us to address important questions about circulating S1P. The answers will provide both increased fundamental knowledge about S1P biology and practical information to guide the further development of S1P-targeted therapeutics.

描述（由申请人提供）： 1-磷酸鞘氨醇 (S1P) 是一种生物活性脂质，由于 S1P 储存在红细胞中，因此在血浆中以三位数纳摩尔水平循环，在全血中以个位数微摩尔水平循环。循环 S1P 参与淋巴细胞运输的强直控制、内皮完整性的维持和心率的控制。血液 S1P 在几分钟内降解。然而，我们既不知道 S1P 从循环中清除的机制，也不知道它如何从细胞转运到血浆。对开发阻断 S1P 合成或作用的疗法的兴趣增加了了解循环 S1P 水平如何调节以及降低循环 S1P 张力的急性和慢性后果的紧迫性。在过去的支持期间，我们发现了新的小分子 S1P 受体激动剂、拮抗剂和合成抑制剂，并开发了针对 S1P 信号传导和代谢进行基因改造的小鼠。此外，我们还增加了复杂的分析化学功能，可以对小样品中的鞘脂种类进行定量。现在，我们建议在这一成功的基础上，使用我们的化学和分子生物学工具更深入地了解 S1P 生物学。具体来说，我们将：（目标 1）确定循环 S1P 水平的范围，测试脂质磷酸酶 LPP1 负责血浆 S1P 降解以及 Spns2 转运 S1P 的假设，以及（目标 2）使用 S1P 合成抑制剂来急剧降低循环 S1P并长期确定对淋巴细胞运输、毛细血管通透性和心率的影响。我们在 S1P 化学生物学方面拥有丰富的经验，我们成功地发现了具有药物特性的 S1P 受体激动剂和拮抗剂，这使我们能够解决有关循环 S1P 的重要问题。这些答案将提供更多有关 S1P 生物学的基础知识和实用信息，以指导 S1P 靶向治疗的进一步开发。