A map of sphingosine 1-phosphate distribution

1-磷酸鞘氨醇分布图

基本信息

批准号：
9888299
负责人：
Susan Ruth Schwab
金额：
$ 42.38万
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：
2017
资助国家：
美国
起止时间：
2017-04-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9888299
关键词：
Address Anti-Inflammatory Agents Antiinflammatory Effect Astrocytes Attention Autoantigens Autoimmune Responses Binding Proteins Blood Circulation Blood Vessels Brain CD8-Positive T-Lymphocytes Cardiac Cardiac Myocytes Cardiovascular system Carrier Proteins Cell Surface Receptors Cell secretion Cells Clinical Code Colitis Complex Dangerousness Data Development Disease Drug Targeting Endothelial Cells Enzymes Equilibrium Experimental Autoimmune Encephalomyelitis FDA approved G-Protein-Coupled Receptors Generations Goals Grant Heart Heart Rate Immune response Immune system In Situ Infection Inflammation Inflammatory Inorganic Phosphate Transporter Intercellular Fluid Interferon Type II Ligands Light Lipids Location Lymph Lymphatic Lymphatic Endothelial Cells Lymphocyte Maps Mass Spectrum Analysis Measurement Metabolic Modeling Movement Multiple Sclerosis Mus Natural Killer Cells Neuraxis Oral Organ Patients Pharmaceutical Preparations Play Production Psoriasis Reporter Role Series Shapes Signal Transduction Sinus Site Source Specificity Sphingosine-1-Phosphate Receptor Spinal Cord T-Lymphocyte T-bet protein Techniques Testing Therapeutic Tissues Travel Vascular Permeabilities Work chemokine cytokine design effector T cell extracellular immune function lymph node medullary portion lymph nodes lymphoid organ migration mouse model novel novel strategies phase II trial prevent protein distribution receptor response side effect small molecule sphingosine 1-phosphate success synthetic enzyme targeted treatment tool trafficking

项目摘要

Project Summary The signaling lipid sphingosine 1-phosphate (S1P) plays critical roles in the immune response. S1P is recognized by five G protein-coupled receptors, which regulate trafficking and cytokine responses of myriad cells including lymphocytes, astrocytes and endothelial cells. Most notably, the abundant S1P in lymph guides T cells out of lymph nodes (LN), where they are initially activated, into circulation, where they can travel to the site of inflammation. FTY720, a drug that targets four of five S1P receptors, was the first FDA-approved oral therapeutic for multiple sclerosis, and second-generation drugs inhibiting S1P signaling have shown promise in psoriasis and colitis. These drugs trap T cells within LN, preventing access to sites of inflammation, and they may have additional important anti-inflammatory effects within diseased tissues. Despite S1P's importance and FTY720's efficacy, many questions remain about how S1P signaling regulates immune responses because we cannot map S1P distribution in tissues. While it is well-established that circulatory S1P directs lymphocyte movement between organs, we understand little about the function of S1P within organs. This is a challenging problem because, in general, we lack tools to chart lipid gradients. A series of elegant studies has shed light on the distribution of protein chemokines by knocking fluorescent reporters into the chemokine- coding locus. But lipids are not encoded genetically, and the complex balance of synthetic enzymes, degrading enzymes, and transporters determines the level of signaling-available lipids. Mass spectrometry has been used to quantify bioactive small molecules, but whole tissue measurements can be misleading because many lipids act both extracellularly as ligands for cell-surface receptors and intracellularly as metabolic intermediates. Moreover, even if interstitial fluid could be extracted from a precise location without inducing inflammation, lipids are generally bound by protein carriers, and it remains unclear which carriers present vs. sequester these lipids from their cognate receptors. To overcome these problems, we have generated a mouse expressing a reporter of signaling-available S1P. To our knowledge, this is the first technique to map signaling lipids in situ. Here, we will use this mouse to address two fundamental questions about S1P gradients within tissues and immune function. In our first aim we will focus on a lymphoid organ. We have chosen LN, where T cells are first activated by tissue infection or auto-antigens before exiting in response to circulatory S1P. We will test the hypothesis that S1P gradients sensed by S1P receptor 5 define LN regions enriched with cells poised to produce IFNγ. In our second aim, we will turn to a non-lymphoid tissue, where effector T cells arrive from circulation. Because of FTY720's clinical success, we will map S1P in the central nervous system (CNS) during experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. We will identify factors that regulate pro-inflammatory S1P in the CNS, which may enable development of spatially targeted therapies that avoid some of FTY720's dangerous side effects.

项目摘要 1-磷酸（S1P）信号脂质鞘氨酸在免疫响应中起关键作用。 S1P是由五个G蛋白偶联受体识别，这些受体调节了众多的运输和细胞因子反应包括淋巴细胞，星形胶质细胞和内皮细胞在内的细胞。最值得注意的是，淋巴细胞中丰富的S1P T细胞从淋巴结（LN）中，最初被激活，进入循环中，可以在其中传播到循环炎症部位。 FTY720是一种针对五个S1P受体中四种的药物，是第一个FDA批准的口服多发性硬化症和抑制S1P信号的第二代药物的治疗性在牛皮癣和结肠炎。这些药物将T细胞捕获在LN中，以防止进入炎症部位，并且它们在解剖组织中可能还具有其他重要的抗炎作用。尽管S1P的重要性和FTY720的效率，关于S1P信号如何调节免疫反应的许多问题仍然存在因为我们无法在组织中绘制S1P分布。虽然有良好的电路S1P指导器官之间的淋巴细胞运动，我们对器官内S1P的功能一无所知。这是一个具有挑战性的问题，因为一般而言，我们缺乏绘制脂质梯度的工具。一系列优雅的研究有通过将荧光记者敲入趋化因子 - 编码基因座。但是脂质并非一般编码，并且合成酶的复杂平衡，降解酶和转运蛋白确定信号可用脂质的水平。质谱法已用于量化生物活性小分子，但整个组织测量可能会引起误导因为许多脂质既是细胞外作为细胞表面受体的配体，又是细胞内的代谢中间体。此外，即使可以从精确位置提取间质流体诱导炎症，脂质通常由蛋白质载体结合，尚不清楚哪些载体目前与这些脂质的同源接收器中的这些脂质。为了克服这些问题，我们有生成了表达信号可用S1P的记者的鼠标。据我们所知，这是第一个原位映射信号脂质的技术。在这里，我们将使用此鼠标来解决两个基本问题大约在组织中的S1P梯度和免疫功能。在我们的第一个目标中，我们将专注于淋巴器官。我们选择了LN，在退出之前，首先通过组织感染或自动抗原激活T细胞对电路S1P的响应。我们将测试以下假设：S1P受体5定义S1P梯度 LN区域富含中毒的细胞产生IFNγ。在我们的第二个目标中，我们将转向非淋巴机组织，效应T细胞从循环中到达。由于FTY720的临床成功，我们将在实验性自身免疫性脑脊髓炎（EAE）期间的中枢神经系统（CNS），小鼠模型多发性硬化症。我们将确定调节中枢神经系统中促炎S1P的因素，这可能使避免FTY720的某些危险副作用的空间靶向疗法的发展。