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：
8079797
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/8079797
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 Injury KRN7000 Lead Life Ligands Link Lipids Liquid substance Liver 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 abstracting 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 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

DESCRIPTION (provided by applicant): 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 S IP 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 of the physiological roles of the 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. PUBLIC HEALTH RELEVANCE: 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. (End of Abstract)

描述（由申请人提供）：该资源的目的是合成各种生物活性鞘氨酸1-磷酸盐（81p）和糖磷脂的变体，这些变体将为NHLBI和其他研究人员提供与肺和血管生物学有关的研究人员的合作者。要制备的化合物包括磷酸手性磷酸和乙烯磷酸化合物的FTY720和C-糖苷的类似物，并具有免疫刺激性糖脂α-基乳糖基酰胺的磷酸化合物和C-糖苷。 FTY720是鞘氨醇的结构类似物，它以其未磷酸化的形式影响许多酶的活性，并且是新的小分子SIP受体受体激动剂中的第一位药物，在其被鞘氨酶激酶-2磷酸化后改变了淋巴细胞流量。糖磷脂脂α-半乳糖基酰胺（Alpha-galcer，也称为KRN7000）是海洋天然产物相相的合成类似物，可激活人类和小鼠不变的天然杀伤剂T细胞以产生免疫调节性细胞因子。磷酸盐和C-半乳糖苷分别是代谢稳定的磷酸盐和糖连接化合物的衍生物。该提案描述了与肺部医学有关的三个项目，这些项目将通过有效脂质介质FTY720和Alpha-Galcer的独特类似物的可用性来促进。具体目的是：AIM 1。通过使用（S）-FTY720-FTY720-乙烯基膦酸酯的类似物（该赠款作为鞘氨酸激酶抑制剂支持的先前研究中鉴定出的铅化合物），抑制人肺动脉平滑肌细胞中的SIP产生和信号传导。 AIM 2。分析人血浆凝胶素在介导S IP和FTY720-磷酸的细胞外生物活性中的作用，这些磷酸通过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类似物作为活的减毒芽孢杆菌 - 塞氏菌（BCG）疫苗的佐剂。具体目的1和2将进一步了解鞘氨酸激酶和SIP信号系统在病理生理学中的生理作用。预计特定的目标3将提供有关开发疫苗具有提高功效的方法的新见解，从而可以控制结核病。公共卫生相关性：该项目将开发新的化学化合物，可以通过对特定靶标的作用来改变细胞反应，从而导致人类疾病和炎症性疾病的治疗性治疗。这些化合物的用途包括开发用于预防肺动脉高压，肺部炎症和肺结核分枝杆菌感染的新方法。（抽象的结尾）