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.

该资源的目标是合成多种生物活性 1-磷酸鞘氨醇变体 (81P) 和鞘糖脂将提供给 NHLBI 和其他研究人员的合作者他们的研究与肺和血管生物学有关。待制备的化合物包括手性 FTY720 的膦酸酯和乙烯基膦酸酯类似物以及免疫刺激剂的 C-糖苷糖脂α-半乳糖神经酰胺。 FTY720 是鞘氨醇的结构类似物，可影响许多非磷酸化形式的酶，是新型小分子 SIP 中的第一种试剂受体激动剂，在被鞘氨醇激酶 2 磷酸化后改变淋巴细胞运输。这鞘糖脂α-半乳糖神经酰胺（α-GalCer，也称为 KRN7000）是一种合成类似物海洋天然产物 Agelasphin，可激活人类和小鼠不变的自然杀伤 T 细胞产生免疫调节细胞因子。膦酸盐和 C-半乳糖苷代谢稳定分别是磷酸酯连接化合物和糖连接化合物的衍生物。该提案描述了三个项目与肺医学相关的研究将通过有效脂质的独特类似物的可用性而得到促进介质 FTY720 和 alpha-GalCer。具体目标是： AIM 1. 抑制 SIP 的产生和信号传导使用 (S)-FTY720-乙烯基膦酸酯（一种先导化合物）类似物对人肺动脉平滑肌细胞进行该化合物在之前的研究中被鉴定为鞘氨醇激酶抑制剂）。目标2。分析人血浆凝溶胶蛋白在介导 SIP 和 FTY720-细胞外生物活性中的作用磷酸盐通过肺内皮细胞和肺上皮细胞中的 G 蛋白偶联受体发挥作用。目的 3. 使用 α-C-GalCer 类似物作为活减毒卡介苗 (BCG) 的佐剂疫苗。具体目标 1 和 2 将进一步加深我们对鞘氨醇生理作用的理解病理生理学中的激酶和 SIP 信号系统。具体目标 3 预计将提供新的深入了解开发疫苗的方法，提高疫苗的功效，从而控制结核病。相关性（参见说明）：该项目将开发新的化合物，这些化合物能够通过作用来改变细胞反应针对特定目标，从而实现人类疾病和炎症性疾病的治疗。这这些化合物的用途包括开发预防肺动脉粥样硬化的新方法高血压、肺部炎症和结核分枝杆菌肺部感染。

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.