Regulation of gene silencing by exogenous sphingosine

外源鞘氨醇对基因沉默的调控

• 批准号: 7256115
• 负责人: EVA M SCHMELZ
• 金额: $ 26.84万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-10 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7256115
• 关键词: Aberrant DNA Methylation; Adhesions; Adverse effects; Affect; Cell Line; Cells; Ceramides; Chemopreventive Agent; Colon Carcinoma; Complex; DNA Methyltransferase; DNA Modification Methylases; Deoxycytidine; Development; Diet; Dose; Down-Regulation; E-Cadherin; Epigenetic Process; Epithelial; Epithelial Cells; Event; Exposure to; Gene Expression; Gene Expression Regulation; Gene Silencing; Genes; Genetic; Goals; Histone Deacetylase; Hydrolysis; Hypermethylation; Immunocompetent; In Vitro; Incidence; Intestines; Knowledge; Lead; Malignant - descriptor; Malignant neoplasm of ovary; Mediating; Methods; Methylation; Modeling; Mus; Neoplasm Metastasis; Numbers; Oral Administration; Ovarian; Pattern; Personal Satisfaction; Pharmaceutical Preparations; Phenotype; Prevention; Prevention strategy; Process; Promoter Regions; Proteins; Regulation; Research; Research Personnel; Role; Sphingolipids; Sphingomyelins; Sphingosine; Staging; Surface; Testing; Thinking; Tumor Promoters; Tumor Suppressor Genes; Tumor Suppressor Proteins; Work; base; cancer cell; cancer prevention; carcinogenesis; cell growth; cell transformation; chemotherapeutic agent; cytotoxic; design; enzyme activity; histone methyltransferase; in vivo; innovation; mortality; mouse model; novel strategies; ovarian cancer prevention; ovarian neoplasm; prevent; promoter; protein expression; tumor; tumor progression; tumorigenic

DESCRIPTION (provided by applicant): Despite tremendous efforts to prevent or cure ovarian cancer, its incidence and high mortality has remained largely unchanged. There are no proven methods of early prevention, and chemotherapeutic agents often are highly cytotoxic and cause severe side effects. We have generated new mouse ovarian surface epithelial (MOSE) cell lines that mimic early stages of ovarian cancer that progress to intermediate and late stages. Aberrant gene methylation accompanies the progression of these cells that can be prevented by sphingosine. Our long-term goal is to understand the regulation of transformed cells by non-toxic doses of sphingolipids, and apply this knowledge to cancer prevention and treatment with orally administered sphingolipids Here we propose to investigate the central hypothesis is that non-toxic doses of sphingosine prevent aberrant DNA methylation of tumor suppressor genes, activate their re-expression and, thereby, prevent or suppress ovarian tumor progression and metastasis. This hypothesis has been formulated based on our preliminary studies that show that sphingosine prevents and/or reverses epigenetic silencing of E-cadherin and lowers the tumorigenic potential of the MOSE cells in vitro. This hypothesis will be tested by pursuing the following specific aims: 1) To determine the mechanisms of how non-toxic doses of sphingosine regulate gene methylation. 2) To determine sphingosine-mediated changes in epigenetic silening that accompanies progression of MOSE cells. 3) To determine to what extent the regulation of epigenetic silencing is associated with the prevention of tumor formation and metastasis by dietary sphingomyelin in a syngeneic model. The proposed research is highly significant because the reversal of epigenetic silencing of tumor suppressors that occurs early in carcinogenesis is a critical step in the prevention of cancer. The proposed studies will provide the mechanistic basis for the development of a chemopreventive and possibly chemotherapeutic strategy using orally administered complex sphingolipids. The proposed studies will also greatly enhance our knowledge on the mechanisms of how long-term exposure to non-toxic concentrations of sphingosine reverses aberrant protein expression in cancer cells.

描述（由申请人提供）：尽管为预防或治疗卵巢癌付出了巨大的努力，但其发病率和高死亡率基本保持不变。目前尚无行之有效的早期预防方法，化疗药物通常具有高度细胞毒性并引起严重的副作用。我们已经产生了新的小鼠卵巢表面上皮（MOSE）细胞系，可以模拟卵巢癌的早期阶段，并进展到中期和晚期。异常的基因甲基化伴随着这些细胞的进展，可以通过鞘氨醇来预防。我们的长期目标是了解无毒剂量的鞘脂对转化细胞的调节，并将这些知识应用于口服鞘脂的癌症预防和治疗。在这里，我们建议研究的中心假设是无毒剂量的鞘氨醇防止肿瘤抑制基因的异常 DNA 甲基化，激活其重新表达，从而预防或抑制卵巢肿瘤的进展和转移。这一假设是根据我们的初步研究提出的，这些研究表明鞘氨醇可以防止和/或逆转 E-钙粘蛋白的表观遗传沉默，并降低体外 MOSE 细胞的致瘤潜力。该假设将通过追求以下具体目标进行检验：1）确定无毒剂量的鞘氨醇如何调节基因甲基化的机制。 2) 确定伴随MOSE细胞进展的鞘氨醇介导的表观遗传沉默变化。 3) 在同基因模型中确定表观遗传沉默的调节与膳食鞘磷脂预防肿瘤形成和转移的相关程度。这项研究非常重要，因为逆转癌发生早期发生的肿瘤抑制因子的表观遗传沉默是预防癌症的关键步骤。拟议的研究将为开发使用口服复合鞘脂的化学预防和可能的化学治疗策略提供机制基础。拟议的研究还将极大地增强我们对长期暴露于无毒浓度的鞘氨醇如何逆转癌细胞中异常蛋白表达的机制的了解。