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.

项目概要信号脂质 1-磷酸鞘氨醇 (S1P) 在免疫反应中发挥着关键作用。被五个 G 蛋白偶联受体识别，这些受体调节多种细胞因子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导管中丰富的 S1P。 T 细胞从淋巴结 (LN) 中被激活，进入循环系统，在那里它们可以到达 FTY720 是一种针对五种 S1P 受体中的四种的药物，是 FDA 批准的第一种口服药物。多发性硬化症的治疗方法和抑制 S1P 信号传导的第二代药物已在以下方面显示出前景：这些药物将 T 细胞困在 LN 内，阻止其进入炎症部位。尽管 S1P 很重要，但它可能在患病组织中具有额外重要的抗炎作用。和 FTY720 的功效，关于 S1P 信号如何调节免疫反应仍然存在许多问题因为我们无法绘制 S1P 在组织中的分布图，尽管循环 S1P 的指导已得到证实。由于淋巴细胞在器官之间的运动，我们对S1P在器官内的功能知之甚少。这是一个具有挑战性的问题，因为总的来说，我们缺乏绘制脂质梯度图表的工具。通过将荧光产生者敲入趋化因子中来揭示蛋白质趋化因子的分布但脂质不是由基因编码的，而且合成酶的复杂平衡，降解酶和转运蛋白决定了信号传导可用脂质的水平。已用于量化生物活性小分子，但整个组织测量可能会产生误导因为许多脂质在细胞外既充当细胞表面受体的配体，又在细胞内充当细胞表面受体的配体。此外，即使可以从精确的位置提取间质液，也无需担心。诱导炎症，脂质通常与蛋白质载体结合，目前尚不清楚哪些载体存在与隔离这些脂质与其同源受体的关系为了克服这些问题，我们有。据我们所知，这是第一个表达可用 S1P 信号的小鼠。原位绘制信号脂质图谱的技术在这里，我们将使用这种鼠标来解决两个基本问题。关于组织内的 S1P 梯度和免疫功能在我们的第一个目标中，我们将关注淋巴器官。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，然后再退出我们将检验 S1P 受体 5 感知的 S1P 梯度定义的假设。 LN 区域富含准备产生 IFNγ 的细胞。在我们的第二个目标中，我们将转向非淋巴细胞。由于 FTY720 的临床成功，我们将在其中绘制 S1P。实验性自身免疫性脑脊髓炎 (EAE) 小鼠模型中的中枢神经系统 (CNS) 我们将确定中枢神经系统中促炎性 S1P 的调节因素，这可能有助于实现多发性硬化症的治疗。开发空间靶向疗法，避免 FTY720 的一些危险副作用。