Ceramide, Membrane Glycolipids and Glycoprotein Expression

神经酰胺、膜糖脂和糖蛋白表达

• 批准号: 7208127
• 负责人: Myles C. Cabot
• 金额: $ 38.11万
• 依托单位: SAINT JOHN'S CANCER INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-01 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7208127
• 关键词: 4-propionyloxy-4-phenyl-N-methylpiperidine; ABCB1 gene; AIDS/HIV problem; ATP-Binding Cassette Transporters; Animal Model; Antibiotics; Apoptosis; Bacteria; Biological Models; Cancer cell line; Carrier Proteins; Cell model; Cells; Ceramide glucosyltransferase; Ceramides; Cerebrosides; Communicable Diseases; Disease; Down-Regulation; Doxorubicin; Drug Kinetics; Drug resistance; Enzymes; Funding; Gangliosides; Gene Expression; Generations; Glucose; Glucosylceramides; Glycolipids; Glycoproteins; Goals; HIV Protease Inhibitors; Human; In Vitro; Knowledge; Lead; Leishmaniasis; Lipid Biochemistry; Lipids; Malaria; Malignant - descriptor; Malignant Neoplasms; Mammary Neoplasms; Membrane; Metabolism; Methods; Mission; Modeling; Molecular and Cellular Biology; Multi-Drug Resistance; Nature; Nitrous Oxide; Outcome; P-Glycoprotein; P-Glycoproteins; Pharmaceutical Preparations; Phenotype; Play; Protein Family; Protein Overexpression; Proteins; Regulation; Research; Research Personnel; Role; Staging; Testing; Therapeutic; Tumor Biology; United States National Institutes of Health; Vertebral column; Vision; Widespread Disease; Work; Xenograft Model; antitumor agent; cancer cell; chemotherapy; clinical effect; concept; drug sensitivity; human disease; improved; in vitro Model; in vivo; inhibitor/antagonist; irradiation; lipid metabolism; malignant breast neoplasm; member; novel strategies; practical application; programs; protein expression; research study; response; tumor; tumor xenograft

DESCRIPTION (provided by applicant): This project will determine the influence of ceramide, ceramide metabolites, and glucosylceramide synthase (GCS) on expression of the multidrug-resistant phenotype, using cancer cells in vitro, and tumor xenographs in vivo, as model systems. GCS catalyzes the formation of glucosylceramide (GC), the building block of higher glycolipids (cerebrosides, gangliosides). Glycolipids such as GC are also substrates for ABC transporter proteins, of which the MDR1 protein, P-glycoprotein (P-gp) is a member. Overexpression of MDR1/P-gp in cells represents a major impediment to effective treatment of many infectious and malignant diseases. Our objective is to improve treatment of disease. If lipids are involved in expression of the MDR1 phenotype, then blocking lipid metabolism at a specific juncture may be a means of limiting multidrug resistance. Many agents - chemotherapy drugs, nitrous oxide, gamma-irradiation - promote an increase in cellular ceramide, which elicits apoptosis. However, high levels of ceramide can also trigger overexpression of GCS due to increased availability of the enzymes lipoidal substrate, leading to elevated levels of GC. Because of the relationship between chemotherapy drugs and ceramide generation, and because high levels of GC are found in multidrug-resistant cancer cells and tumors, we hypothesize that lipids enhance expression of the multidrug-resistant phenotype. This enhancement would dull cellular responses to antibiotics, antitumor agents, and HIV protease inhibitors. The aims of this proposal are: 1. to determine the influence of GCS on MDR1/P-gp expression; 2. to determine the influence of GCS modulation by PPMP, a GCS inhibitor, on MDR1/P-gp expression and response to doxorubicin in an in vitro multidrug-resistant breast tumor xenograft model; 3. to determine the influence of lipids (ceramide, glycolipids) on expression of the multidrug-resistant phenotype, 4. to determine the influence of chemotherapy drugs on GCS and MDR1 expression. We have ordered the Aims to facilitate testing of proof of principle. Aim 1 will demonstrate the power of targeting GCS as an approach to limiting MDR1 expression, using in vitro models. Aim 2, using animal models, will evaluate the power of targeting GCS as an approach to treating drug resistance, in vivo. Aims 3 and 4 focus on mechanisms, and their outcomes will not detract from the possible therapeutic value of the study. This is the first study to investigate the influence of lipids on the multidrug-resistant phenotype. The results could lead to improved treatment of HIV/AIDS, malignant disorders, and bacterial and parasitic infectious diseases, as treatment of these diseases is classically hindered by drug resistance.

描述（由申请人提供）：该项目将确定神经酰胺，神经酰胺代谢产物和葡萄糖基酶合酶（GC）对使用体外癌细胞的多种耐药性表型的表达，并在体内使用肿瘤 - 谱仪作为模型系统。 GCS催化葡萄糖基酰胺（GC）的形成，葡萄糖基酰胺（GC）是高糖脂的基础（大脑，神经苷酸）。糖脂（例如GC）也是ABC转运蛋白的底物，其中MDR1蛋白P-糖蛋白（P-GP）是成员。细胞中MDR1/P-GP的过表达代表了有效治疗许多传染病和恶性疾病的主要障碍。我们的目标是改善疾病的治疗。如果脂质参与MDR1表型的表达，则在特定关头处阻断脂质代谢可能是限制多药电阻的一种手段。许多药物 - 化学疗法药物，一氧化二氮，γ-辐照 - 促进了细胞神经酰胺的增加，这会引起凋亡。然而，高水平的神经酰胺还可以触发GC的过表达，这是由于脂类底物的可用性增加，从而导致GC水平升高。由于化学疗法药物与神经酰胺的产生之间的关系，并且由于在多药耐药性癌细胞和肿瘤中发现了高水平的GC，因此我们假设脂质增强了多药耐药表型的表达。这种增强将使细胞对抗生素，抗肿瘤剂和HIV蛋白酶抑制剂的反应暗淡。该提案的目的是：1。确定GC对MDR1/p-gp表达的影响； 2。为了确定GCS抑制剂PPMP对MDR1/P-GP表达的影响以及在体外耐多药耐药性乳腺肿瘤异种移植模型中对阿霉素的反应； 3。确定脂质（神经酰胺，糖脂）对多药耐药表型表达的影响，4。确定化学疗法药物对GCS和MDR1表达的影响。我们已下令促进原理证明的测试。 AIM 1将证明使用体外模型将靶向GC作为限制MDR1表达的方法。 AIM 2使用动物模型，将评估靶向GC作为治疗耐药性的方法，在体内。目标3和4关注机制，其结果不会损害研究的可能治疗价值。这是研究脂质对多药耐药表型的影响的第一项研究。结果可能会导致对艾滋病毒/艾滋病，恶性疾病以及细菌和寄生性传染病的治疗改善，因为这些疾病的治疗受到耐药性的限制。