Synthesis of Novel Bioactive Sphingolipids as a Resource

新型生物活性鞘脂作为资源的合成

• 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
• 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; 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

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。