权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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.

项目摘要信号脂质鞘氨醇1-磷酸（S1 P）在免疫应答中起着关键作用。S1 P是由五个G蛋白偶联受体识别，这些受体调节无数细胞的运输和细胞因子反应。细胞，包括淋巴细胞、星形胶质细胞和内皮细胞。最值得注意的是，淋巴管中丰富的S1 P T细胞从淋巴结（LN）中出来，在那里它们最初被激活，进入循环，在那里它们可以旅行到淋巴结。炎症部位。FTY 720是一种靶向五种S1 P受体中的四种的药物，是FDA批准的第一种口服药物。治疗多发性硬化症，第二代药物抑制S1 P信号已显示出希望，牛皮癣和结肠炎。这些药物将T细胞捕获在LN内，阻止其进入炎症部位，可能在患病组织内具有额外的重要抗炎作用。尽管S1 P的重要性和FTY 720的功效，关于S1 P信号传导如何调节免疫应答的许多问题仍然存在因为我们无法绘制S1 P在组织中的分布。虽然众所周知，循环S1 P指导淋巴细胞在器官间的运动，我们对S1 P在器官内的功能了解甚少。这是一这是一个具有挑战性的问题，因为通常我们缺乏绘制脂质梯度的工具。一系列优雅的研究通过将荧光报告基因敲入趋化因子来揭示蛋白趋化因子的分布- 编码基因座但是脂质不是由基因编码的，合成酶的复杂平衡，降解酶和转运蛋白决定了信号可用脂质的水平。质谱已经被用来量化生物活性小分子，但整个组织的测量可能会产生误导因为许多脂质在细胞外作为细胞表面受体的配体，代谢中间产物此外，即使可以从精确的位置提取组织液，诱导炎症，脂质通常与蛋白质载体结合，但仍不清楚哪些载体将这些脂质与它们的同源受体隔离。为了解决这些问题，我们产生表达信号可用S1 P的报告基因的小鼠。据我们所知，这是第一个技术来映射信号脂质原位。在这里，我们将使用这款鼠标来解决两个基本问题关于组织内S1 P梯度和免疫功能。在我们的第一个目标，我们将集中在一个淋巴器官。我们选择了LN，其中T细胞首先被组织感染或自身抗原激活，然后退出淋巴结。对循环S1 P的反应。我们将检验S1 P受体5感受到的S1 P梯度定义了富含准备产生IFNγ的细胞的LN区域。在我们的第二个目标中，我们将转向非淋巴组织，其中效应T细胞从循环到达。由于FTY 720的临床成功，我们将在实验性自身免疫性脑脊髓炎（EAE）小鼠模型中枢神经系统（CNS）多发性硬化症我们将确定调节CNS中促炎性S1 P的因素，这可能使开发空间靶向疗法，避免FTY 720的一些危险副作用。