Synthesis of Novel Bioactive Sphingolipids as a Resource

新型生物活性鞘脂作为资源的合成

基本信息

批准号：
8424276
负责人：
ROBERT BITTMAN
金额：
$ 19.38万
依托单位：
QUEENS COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-02-06 至 2014-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8424276
关键词：
Actins Adjuvant Adult Adult Respiratory Distress Syndrome Affect Agonist Albumins Antigen Presentation Antigen-Presenting Cells Antigens Antitubercular Agents Apoptosis Astrocytes Atomic Force Microscopy Attenuated BCG Vaccine Binding Biological Assay Biology Blood Platelets Blood Vessels C-glycoside Calmette-Guerin Bacillus Cell Proliferation Cell Survival Cell Wall Cell physiology Cell surface Cells Ceramides Cerebrospinal Fluid Chemicals Chronic Clinical Collaborations Complex Data Dendritic Cells Depressed mood Disease Endothelial Cells Endothelium Enzymes Epithelial Epithelial Cells Equilibrium Erythrocytes Extracellular Fluid Extracellular Protein Extracellular Space Fluorescence Functional disorder G-Protein-Coupled Receptors Galactose Galactosides Galactosylceramides Gelsolin Genus Mycobacterium Glycolipids Glycosphingolipids Goals Grant Growth Factor Inhibition Human Hypoxia Immune Immune response In Vitro Infection Inflammatory Inhibition of Apoptosis Instruction KRN7000 Lead Life Ligands Link Lipids Liquid substance Lung Lung Inflammation Lymphocyte Lysophospholipids Malaria Measures Mediating Membrane Methods Molecular Mus Mycobacterium tuberculosis Mycolic Acid National Heart, Lung, and Blood Institute Pathway interactions Phosphatidic Acid Physiological Plasma Prevention Principal Investigator Process Production Property Propylene Glycols Protein Isoforms Protein Phosphatase 2A Regulatory Subunit PR53 Protein phosphatase Proteins Public Health Pulmonary Tuberculosis Pulmonology Regulation Reporting Research Personnel Resources Role Route SPHK1 enzyme Sepsis Signal Pathway Signal Transduction Smooth Muscle Myocytes Solubility Sphingolipids Sphingosine Sphingosine-1-Phosphate Receptor Sugar Phosphates Surface System T-Cell Receptor T-Lymphocyte Testing Therapeutic Therapeutic Intervention Therapeutic Uses Tuberculosis Tuberculosis Vaccines United States National Institutes of Health Vaccines Variant Vascular remodeling absorption alpha-galactosylceramide analog anomer arterial remodeling base cell envelope cell type cytokine extracellular genetic regulatory protein human disease improved inhibitor/antagonist innovation inorganic phosphate insight interest killer T cell lipid mediator liver injury lysophosphatidic acid macrophage marine natural product mycobacterial novel novel strategies pathogen petroleum ether phosphonate programs pulmonary arterial hypertension response small molecule sphingosine 1-phosphate sphingosine kinase tool trafficking

项目摘要

The goal of this resource is to synthesize a wide range of variants of bioactive sphingosine 1-phosphate (81P) and glycosphingolipids that will be made available for collaborators with NHLBI and other investigators whose studies are pertinent to lung and vascular biology. The compounds to be prepared include chiral phosphonate and vinylphosphonate analogs of FTY720 and C-glycosides ofthe immunostimulatory glycolipid alpha-galactosylceramide. FTY720 is a structural analog of sphingosine that affects the activities of many enzymes in its unphosphorylated form, and is the first agent in a new class of small molecule SIP receptor agonists that alters lymphocyte traffic after it is phosphorylated by sphingosine kinase-2. The glycosphingolipicj alpha-galactosylceramide (alpha-GalCer, also known as KRN7000) is a synthetic analog of the marine natural product agelasphin that activates both human and mouse invariant natural killer T cells to produce immunoregulatory cytokines. Phosphonates and C-galactosides are metabolically stabilized derivatives of phosphate- and sugar-linked compounds, respectively. This proposal describes three projects related to pulmonary medicine that will be facilitated by the availability of unique analogs of the potent lipid mediators FTY720 and alpha-GalCer. The specific aims are: AIM 1. Inhibit SIP production and signaling in human pulmonary arterial smooth muscle cells by using analogs of (S)-FTY720-vinylphosphonate (a lead compound identified in previous studies supported by this grant as an inhibitor of sphingosine kinase). AIM 2. Analyze the role of human plasma gelsolin in mediating the extracellular bioactivity of SIP and FTY720- phosphate, which act through the G protein-coupled receptors, in lung endothelial and lung epithelial cells. AIM 3. Use alpha-C-GalCer analogs as adjuvants forthe live attenuated Bacillus Calmette-Guerin (BCG) vaccine. Specific aims 1 and 2 will further our understanding ofthe physiological roles ofthe sphingosine kinase and the SIP signaling system in pathophysiology. Specific aim 3 is anticipated to provide new insights into methods for developing vaccines with improved efficacy leading to control of tuberculosis. RELEVANCE (See instructions): This project will develop new chemical compounds that have the ability to alter cellular responses by acting on specific targets, leading to therapeutic treatments of human diseases and inflammatory disorders. The uses of the compounds include developing new approaches for prevention of pulmonary arterial hypertension, lung inflammation, and pulmonary infection from Mycobacterium tuberculosis.

该资源的目的是合成各种生物活性鞘氨醇1-磷酸的变体（81p）和糖脂果脂，将为NHLBI和其他研究人员提供合作者其研究与肺和血管生物学有关。要准备的化合物包括手性免疫刺激性的FTY720和C-糖苷的膦酸酯和偶然膦酸酯类似物糖脂α-半乳糖基酰胺。 FTY720是鞘氨醇的结构类似物，影响了许多酶以其未磷酸化的形式，是新的小分子sip中的第一个药物受体激动剂会通过鞘氨醇激酶-2磷酸化后改变淋巴细胞流量。这糖磷脂脂蛋白α-半乳糖基酰胺（α-甘油，也称为KRN7000）是一种合成类似物海洋天然产物伴阵环阵环激活人和小鼠不变的天然杀手T细胞产生免疫调节细胞因子。磷酸盐和C-半乳糖苷是代谢稳定的分别是磷酸盐和糖连接化合物的衍生物。该建议描述了三个项目与肺部药物有关，这将通过有效脂质的独特类似物的可用性来促进介质FTY720和α-Galcer。具体目的是：AIM 1。抑制SIP的产生和信号传导人类肺动脉平滑肌细胞使用（S）-fty720-乙烯膦酸盐的类似物（铅该赠款支持的先前研究中确定的化合物是鞘氨醇激酶的抑制剂）。目标2。分析人血浆凝胶素在介导SIP和FTY720-的细胞外生物活性中的作用磷酸盐通过G蛋白偶联受体起作用，在肺内皮和肺上皮细胞中。 AIM 3。使用α-C-Galcer类似物作为活片状杆状芽孢杆菌（BCG）的佐剂疫苗。具体目的1和2将进一步了解鞘氨醇的生理作用病理生理学中的激酶和SIP信号系统。预计具体目标3将提供新的对开发具有提高功效的疫苗方法的方法，从而控制了结核病。相关性（请参阅说明）：该项目将开发新的化合物，具有通过作用来改变细胞反应的能力关于特定靶标，导致人类疾病和炎症性疾病的治疗性治疗。这化合物的使用包括开发预防肺动脉的新方法结核分枝杆菌的高血压，肺部炎症和肺部感染。

项目成果

期刊论文数量（36）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Enzymatic oxidation of cholesterol: properties and functional effects of cholestenone in cell membranes.

DOI：
10.1371/journal.pone.0103743
发表时间：
2014
期刊：
PloS one
影响因子：
3.7
作者：
Neuvonen M;Manna M;Mokkila S;Javanainen M;Rog T;Liu Z;Bittman R;Vattulainen I;Ikonen E
通讯作者：
Ikonen E

Lipid Phase Separation and Protein-Ganglioside Clustering in Supported Bilayers Are Induced by Photorelease of Ceramide.

DOI：
10.1039/c3sm50240f
发表时间：
2013-05-21
期刊：
Soft matter
影响因子：
3.4
作者：
Carter Ramirez DM;Kim YA;Bittman R;Johnston LJ
通讯作者：
Johnston LJ

Synthesis of (S)-FTY720 vinylphosphonate analogues and evaluation of their potential as sphingosine kinase 1 inhibitors and activators.

DOI：
10.1016/j.bmc.2013.02.042
发表时间：
2013-05-01
期刊：
Bioorganic & medicinal chemistry
影响因子：
3.5
作者：
Liu Z;MacRitchie N;Pyne S;Pyne NJ;Bittman R
通讯作者：
Bittman R

Cholesterol's aliphatic side chain modulates membrane properties.

DOI：
10.1002/anie.201306753
发表时间：
2013-12-02
期刊：
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
影响因子：
16.6
作者：
Scheidt, Holger A.;Meyer, Thomas;Nikolaus, Joerg;Baek, Dong Jae;Haralampiev, Ivan;Thomas, Lars;Bittman, Robert;Mueller, Peter;Herrmann, Andreas;Huster, Daniel
通讯作者：
Huster, Daniel

Synthesis of immunostimulatory alpha-C-galactosylceramide glycolipids via Sonogashira coupling, asymmetric epoxidation, and trichloroacetimidate-mediated epoxide opening.