Molecular Pharmacology of Sphingosine 1-Phosphate

1-磷酸鞘氨醇的分子药理学

• 批准号: 8206342
• 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
• 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/8206342
• 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

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. PUBLIC HEALTH RELEVANCE: Sphingosine 1-phosphate (S1P) is a bioactive lipid that circulates in the bloodstream. The circulating S1P influences the immune system by affecting lymphocyte trafficking, helps to keep small blood vessels from leaking and may tonically depress heart rate. However, we know little about how blood S1P levels are controlled or even the range of S1P concentrations in the blood, but we do know that blood S1P is in a state of rapid flux. Due to the recent approval of a drug that mimics S1P for treating multiple sclerosis, there is a surge of interest in drugs that affect S1P signaling. Among these are investigational drugs that decrease S1P levels by inhibiting its synthesis. Using rodents as surrogates for humans, the research proposed will determine the range of normal S1P levels and explore mechanisms whereby S1P is transported from cells to plasma and how S1P is destroyed in plasma. Further, we will determine the effects of blocking S1P synthesis which rapidly lowers circulating S1P levels on lymphocyte trafficking, vascular leakage and heart rate. By executing this experimental plan, we will learn both about basic S1P biology and predict possible adverse events that accompany therapeutic agents designed to block S1P synthesis.

描述（由申请人提供）：1-磷酸盐（S1P）是一种生物活性脂质，在血浆中的三位数纳摩尔水平循环，由于S1P在偶联细胞中的存储而导致的全血中的单数微摩尔水平。循环S1P与淋巴细胞运输的补品控制，内皮完整性的维持和心率控制。血液S1P的时间为几分钟。但是，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移到血浆。对开发阻断S1P合成或作用的治疗剂的兴趣增加了对如何调节循环S1P水平的理解以及降低循环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，并开发了用于S1P信号传导和代谢的遗传改变的小鼠。此外，我们添加了复杂的分析化学能力，可以定量小样品中的鞘脂种类。现在，我们建议通过使用我们的化学和分子生物学工具来更深入地了解S1P生物学。具体而言，我们将：（目标1）确定循环S1P水平的范围，测试脂质磷酸酶LPP1负责等离子体S1P降解的假设，SPNS2转运S1P，并且（AIM 2）使用S1P合成抑制剂急性地循环S1P敏感并长期确定对淋巴细胞运输，毛细血管渗透性和心率的影响。我们在S1P化学生物学方面的丰富经验，这是我们在发现具有类似药物特性的S1P受体激动剂和拮抗剂方面证明的，这使我们能够解决有关循环S1P的重要问题。答案将提供有关S1P生物学的越来越多的基本知识和实用信息，以指导以S1P为目标的治疗疗法的进一步发展。 公共卫生相关性：1-磷酸盐（S1P）是一种在血液中循环的生物活性脂质。循环的S1P通过影响淋巴细胞运输来影响免疫系统，有助于防止小血管泄漏，并可能抑制心率。但是，我们对血液S1P水平的控制或血液中S1P浓度的范围却一无所知，但我们确实知道血液S1P处于快速通量状态。由于最近批准了一种模仿S1P治疗多发性硬化症的药物，因此对影响S1P信号传导的药物感兴趣。其中包括通过抑制其合成来降低S1P水平的研究性药物。提出的研究将使用啮齿动物作为人类的替代物，将确定正常S1P水平的范围，并探索S1P从细胞转移到血浆的机制，以及如何在血浆中破坏S1P。此外，我们将确定阻断S1P合成的影响，该合成迅速降低了循环S1P水平对淋巴细胞运输，血管泄漏和心率的影响。通过执行该实验计划，我们将既了解基本的S1P生物学，又可以预测伴随旨在阻止S1P合成的治疗剂的不良事件。